N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists

ABSTRACT

Compounds represented by Formula (I):  
                 
 
     or pharmaceutically acceptable salts thereof, are effective as NMDA NR2B antagonists useful for relieving pain.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

[0001] This invention relates to N-substituted nonarylheterocyclo amidylcompounds. In particular, this invention relates to N-substitutednonarylheterocyclo amidyl compounds that are effective as NMDA NR2Bantagonists useful for relieving pain.

[0002] Ions such as glutamate play a key role in processes related tochronic pain and pain-associated neurotoxicity—primarily by actingthrough N-methyl-D-aspartate (“NMDA”) receptors. Thus, inhibition ofsuch action—by employing ion channel antagonists, particularly NMDAantagonists—can be beneficial in the treatment and control of pain.

[0003] Known NMDA antagonists include ketamine, dextromophan, and3-(2-carboxypiperazin4-yl)-propyl-1-phosphonic acid (“CPP”). Althoughthese compounds have been reported (J. D. Kristensen, et al., Pain,51:249-253 (1992); P. K. Eide, et al., Pain, 61:221-228 (1995); D. J.Knox, et al., Anaesth. Intensive Care 23:620-622 (1995); and M. B. Max,et al., Clin. Neuropharmacol. 18:360-368 (1995)) to produce symptomaticrelief in a number of neuropathies including postherpetic neuralgia,central pain from spinal cord injury, and phantom limb pain, widespreaduse of these compounds is precluded by their undesirable side effects.Such side effects-at analgesic doses include psychotomimetic effectssuch as dizziness, headache, hallucinations, dysphoria, and disturbancesof cognitive and motor function. Additionally, more severehallucinations, sedation, and ataxia are produced at doses onlymarginally higher than analgesic doses. Thus, it would be desirable toprovide novel NMDA antagonists that are absent of undesirable sideeffects or that produce fewer and/or milder side effects.

[0004] NMDA receptors are heteromeric assemblies of subunits, of whichtwo major subunit families designated NR1 and NR2 have been cloned.Without being bound by theory, it is generally believed that the variousfunctional NMDA receptors in the mammalian central nervous system(“CNS”) are only formed by combinations of NR1 and NR2 subunits, whichrespectively express glycine and glutamate recognition sites. The NR2subunit family is in turn divided into four individual subunit types:NR2A, NR2B, NR2C, and NR2D. T. Ishii, et al., J. Biol. Chem.,268:2836-2843 (1993), and D. J. Laurie et al., Mol. Brain Res., 51:23-32(1997) describe how the various resulting combinations produce a varietyof NMDA receptors differing in physiological and pharmacologicalproperties such as ion gating properties, magnesium sensitivity,pharmacological profile, as well as in anatomical distribution.

[0005] For example, while NR1 is found throughout the brain, NR2subunits are differentially distributed. In particular, it is believedthat the distribution map for NR2B lowers the probability of sideeffects while producing pain relief. For example, S. Boyce, et al.,Nettrophannacology, 38:611-623(1999) describes the effect of selectiveNMDA NR2B antagonists on pain with reduced side effects. Thus, it wouldbe desirable to provide novel NMDA antagonists that target the NR2Breceptor. Such antagonists would be useful in the treatment of pain,migraine, depression, anxiety, schizophrenia, Parkinson's disease,stroke, glaucoma, or tinitis—maladies that are amenable to ameliorationthrough inhibition of NMDA NR2B receptors.

[0006] U.S. Pat. No. 6,020,347 and International Patent PublicationWO99/25685 describes 4-substituted-4-piperidine carboxamide derivativesthat are antagonists of VLA-4 (“Very Late Antigen-4”). InternationalPatent Publication WO 01/00207 describes substituted pyrimidinecompounds that are inhibitors of tyrosine kinases. International PatentPublication WO 00/61551 describes oxopyrimidinealkanoate compounds thatare integrin-receptor ligands. International Patent Publication EP604800 describes carboxyalkyl-phenyl aminocarbonyl-phenyl-piperidinecompounds that are blood platelet aggregation inhibitors. InternationalPatent Publication EP 611660 describes benzimidazoles, xanthines, andanalogs as tissue aggregation inhibitors. International PatentPublication EP 771799 and U.S. Pat. No. 5,861,396 describe purin-6-onederivatives for the treatment of cardiovascular and urogenital diseases.International Patent Publication WO94/21615 describesbenzimidazole-piperidine compounds utilized as dopamine D4 antagonists.German Patent No. DE4241632 describes substituted phenyl orcyclohexyl-carboxylic acid derivatives that inhibit cell aggregation.

[0007] International Patent Publication WO 00/25786 describesheterocyclic potassium channel inhibitors. International PatentPublication WO 00/08015 describes non-peptidic amino derivatives thatare follicle stimulating hormone agonists for the treatment ofinfertility. International Patent Publication WO 98/46589 describesindazole amide compounds as serotoninergic agents. International PatentPublication WO 98/05336 describes compounds that are inhibitors ofcysteine protease. International Patent Publication WO 98/04913describes pharmacophore models of integrin VLA-4 inhibitors.International Patent Publication WO 97/45119 describes the use ofsubstance P antagonists for treating social phobia. International PatentPublication WO 97/28141 describes aromatic piperazines derived fromsubstituted cycloazanes. International Patent Publication WO 97/28139describes naphthylpiperazines derived from substituted cycloazanes.International Patent Publication WO 96/34856 describes2-ureido-benzamide derivatives. International Patent Publication WO96/10035 describes inhibitors of farnesyl-protein transferase.International Patent Publication WO 94/20062 describes balanoids.International Patent Publication WO 94/14776 describes bicyclicfibrinogen antagonists. International Patent Publication EP 532456describes 1-acylpiperidine derivatives used as substance-P antagonists.International Patent Publication WO/19709 describes imidazolylbenzoylsubstituted heterocycles. Japanese Patent Publication JP 10120644describes 2-ureido-benzamide derivatives for treating ACAT-relateddiseases. International Patent Publication WO 00/11002 describes9-dialkylamino purinone derivatives. International Patent Publication WO98/31669 describes arylpiperazine antidepressants derived frompiperidine. International Patent Publication WO 98/31677 describesaromatic amines derived from cyclic amines. R. D. Clark et al., J. Med.Chem., 26:855-861(1983) describes antihypertensive 9-subtituted1-oxa-4,9-diazaspiro[5.5]undecan-3-ones.

[0008] Phenol compounds described as NMDA antagonists are described inU.S. Pat. Nos. 5,306,723 and 5,436,255, and in International PatentPublications WO91/17156, WO92/19502, WO93/02052, WO96/37226, and EP441506. Benzyl piperidine substituted with phenols or imidazoles aredescribed in Z.-L. Zhou, et al., J. Medicinal Chemistry,42:2993-3000(1999); T. F. Gregory, et al., Poster #94, 218^(th) NationalMeeting American Chemical Society, New Orleans, La., Aug. 22-26, 1999.Other NMDA NR2B selective compounds are described in European PatentPublication EP 787493 and J. N. C. Kew et al., British J. Pharmacol.,123:463(1998). However, there continues to be a need for novel NMDAantagonists that target the NR2B receptor.

SUMMARY OF THE INVENTION

[0009] The present invention relates to N-substitutednonarylheterocyclic compounds represented by Formula (I):

[0010] or pharmaceutically acceptable salts thereof. The presentinvention also forms pharmaceutical compositions utilizing thecompounds. Further, this invention includes novel methods to treat painby utilizing the compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The compounds of this invention are represented by Formula (I):

[0012] or pharmaceutically acceptable salts thereof, wherein

[0013] NonAr is a nonaromatic 5-7 membered ring containing a) 1 nitrogenring atom, b) 2 nitrogen ring atoms, c) 1 nitrogen and 1 oxygen ringatom, or d) 1 nitrogen and 1 sulfur ring atom, wherein the remainingring atoms are carbon;

[0014] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen; or

[0015] A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl,thiazolyl, thiadiazolyl, oxazolyl, or isoxazolyl, each optionallysubstituted with 1-3 substituents, each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl,phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

[0016] A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted with 1-5 substituents; each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl—N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)—C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)—C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1-5—OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5—OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

[0017] A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

[0018] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂—wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0019] B is

[0020] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0021] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0022] In one aspect, the compounds of this invention are represented byFormula (I) or pharmaceutically acceptable salts thereof, wherein

[0023] NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0024] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—CO₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂-C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen; or

[0025] A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl,thiazolyl, thiadiazolyl, oxazolyl, or isoxazolyl, each optionallysubstituted with 1-3 substituents, each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl,phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

[0026] A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted with 1-5 substituents; each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1-5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

[0027] A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

[0028] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0029] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0030] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0031] In an embodiment of the first aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

[0032] NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0033] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(CO alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen;

[0034] B is aryl(CH₂)₀₋₃—O—(CH₂)o₂—C(O),heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0035] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0036] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0037] In another aspect of the first aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

[0038] NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0039] A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl,thiazolyl, thiadiazolyl, oxazolyl, or isoxazolyl, each optionallysubstituted with 1-3 substituents, each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl,phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl;

[0040] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0041] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0042] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0043] In still another embodiment of the first aspect, the compounds ofthis invention are represented by Formula (I) or pharmaceuticallyacceptable salts thereof, wherein

[0044] NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0045] A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted with 1-5 substituents; each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₄alkoxy,(CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—CO₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(CO₅alkyl)—C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1-5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O;

[0046] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0047] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0048] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0049] In another embodiment of the first aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

[0050] NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0051] A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

[0052] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0053] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0054] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0055] In a second aspect, the compounds of this invention arerepresented by Formula (I) or pharmaceutically acceptable salts thereof,wherein

[0056] NonAr is a nonaromatic 5 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0057] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen; or

[0058] A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl,thiazolyl, thiadiazolyl,oxazolyl, or isoxazolyl, each optionallysubstituted with 1-3 substituents, each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl,phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

[0059] A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted with 1-5 substituents; each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—, —SO₂—C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1-5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

[0060] A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

[0061] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0062] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0063] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0064] In an embodiment of the second aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

[0065] NonAr is a nonaromatic 5 membered ring containing 1 nitrogen ringatom, wherein the remaining ring atoms are carbon;

[0066] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(CO alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen;

[0067] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0068] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0069] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0070] In a third aspect, the compounds of this invention arerepresented by Formula (I) or pharmaceutically acceptable salts thereof,wherein

[0071] NonAr is a nonaromatic 6 membered ring containing 2 nitrogen ringatoms, wherein the remaining ring atoms are carbon;

[0072] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen; or

[0073] A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl,thiazolyl, thiadiazolyl, oxazolyl, or isoxazolyl, each optionallysubstituted with 1-3 substituents, each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl,phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

[0074] A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted with 1-5 substituents; each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy,(CH₃)₂N—(CH₂)₂—, —SO₂—C₁₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)—C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)—C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1-5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5—OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

[0075] A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

[0076] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0077] B is

[0078] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0079] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0080] In an embodiment of the third aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

[0081] NonAr is a nonaromatic 6 membered ring containing 2 nitrogen ringatoms, wherein the remaining ring atoms are carbon;

[0082] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)13C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl, —O—C₁₋₄alkylphenyl, orhydroxyiminoethyl; any alkyl optionally substituted with 1-6 —OH orhalogen;

[0083] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0084] B is

[0085] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0086] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0087] In a fourth aspect, the compounds of this invention arerepresented by Formula (I) or pharmaceutically acceptable salts thereof,wherein NonAr is a nonaromatic 6 membered ring containing 1 nitrogenring atom and 1 oxygen ring atom, wherein the remaining ring atoms arecarbon;

[0088] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁ 4alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen; or

[0089] A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl,thiazolyl, thiadiazolyl, oxazolyl, or isoxazolyl, each optionallysubstituted with 1-3 substituents, each substituent independently is—C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, —C₁₋₄alkoxyl,phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —C₁₋₄hydroxyalkyl; or

[0090] A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, eachoptionally substituted with 1-5 substituents; each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl, —C₁₄alkoxy,(CH₃)₂N—(CH₂)₂—, —SO₂—C₁₄alkyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)-C₀₋₄alkylthiaphenyl, dimethoxyphenyl—CH₂—NH—; any phenyloptionally substituted with 1-5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or

[0091] A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN;

[0092] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0093] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0094] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0095] In an embodiment of the fourth aspect, the compounds of thisinvention are represented by Formula (I) or pharmaceutically acceptablesalts thereof, wherein

[0096] NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ringatom and 1 oxygen ring atom, wherein the remaining ring atoms arecarbon;

[0097] A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl, —C₀₋₄alkyl-N(COalkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂-C₁₋₄alkyl, —O—C₁₋₄alkylphenyl, orhydroxyiminoethyl; any alkyl optionally substituted with 1-6 —OH orhalogen;

[0098] B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

[0099] wherein the phenyl is optionally substituted by 1-3 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and

[0100] X is H, OH, F, C₁₋₄alkyl, C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl),phenyl, or ═O.

[0101] The term “cycloalkyl” means carbocycles containing noheteroatoms, and includes mono-, bi- and tricyclic saturatedcarbocycles, as well as fused ring systems. Such fused ring systems caninclude one ring that is partially or fully unsaturated such as abenzene ring to form fused ring systems such as benzofused carbocycles.Cycloalkyl includes such fused ring systems as spirofused ring systems.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl,fluorenyl, 1,2,3,4-tetrahydronaphthalenyl and the like. Similarly,“cycloalkenyl” means carbocycles containing no heteroatoms and at leastone non-aromatic C-C double bond, and include mono-, bi- and tricyclicpartially saturated carbocycles, as well as benzofused cycloalkenes.Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

[0102] The term “cycloalkyloxy” unless specifically stated otherwiseincludes a cycloalkyl group connected to the oxy connecting atom.

[0103] The term “alkoxy” unless specifically stated otherwise includesan alkyl group connected to the oxy connecting atom.

[0104] The term “aryl” unless specifically stated otherwise includesmultiple ring systems as well as single ring systems such as, forexample, phenyl or naphthyl.

[0105] The term “aryloxy” unless specifically stated otherwise includesmultiple ring systems as well as single ring systems such as, forexample, phenyl or naphthyl, connected through the oxy connecting atomto the connecting site.

[0106] The term “C₀-C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2,1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atomsubstituent when the alkyl is a terminus moiety. An alkyl with no carbonatoms is a direct bond when the alkyl is a bridging moiety.

[0107] The term “hetero” unless specifically stated otherwise includesone or more O, S, or N atoms. For example, heterocycloalkyl andheteroaryl include ring systems that contain one or more O, S, or Natoms in the ring, including mixtures of such atoms. The heteroatomsreplace ring carbon atoms. Thus, for example, a heterocycloC₅alkyl is afive membered ring containing from 5 to no carbon atoms.

[0108] Examples of heteroaryl include, for example, pyridinyl,quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl,pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl.

[0109] The term “heteroaryloxy” unless specifically stated otherwisedescribes a heteroaryl group connected through an oxy connecting atom tothe connecting site.

[0110] Examples of heteroaryl(C₁₋₆)alkyl include, for example,furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl,oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl,thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl,oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl,thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl,tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl,isoquinolinylmethyl and quinoxalinylmethyl.

[0111] Examples of heterocycloC₃₋₇alkyl include, for example,azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl,morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one,piperidin-2-one, and thiomorpholinyl.

[0112] The term “N-heterocycloC₄₋₇alkyl” describes nonaryl heterocycliccompounds having 3-6 carbon atoms and one nitrogen atom forming thering. Examples include azetidinyl, pyrrolidinyl, piperidinyl, andperhydroazepinyl.

[0113] Examples of aryl(C₁₋₆)alkyl include, for example,phenyl(C₁₋₆)alkyl, and naphthyl(C₁₋₆)alkyl.

[0114] Examples of heterocycloC₃₋₇alkylcarbonyl(C₁₋₆)alkyl include, forexample, azetidinyl carbonyl(C₁₋₆)alkyl, pyrrolidinylcarbonyl(C₁₋₆)alkyl, piperidinyl carbonyl(C₁₋₆)alkyl, piperazinylcarbonyl(C₁₋₆)alkyl, morpholinyl carbonyl(C₁₋₆)alkyl, andthiomorpholinyl carbonyl(C₁₋₆)alkyl.

[0115] The term “amine” unless specifically stated otherwise includesprimary, secondary and tertiary amines.

[0116] Unless otherwise stated, the term “carbamoyl” is used to include—NHC(O)OC₁—C₄alkyl, and —OC(O)NHC₁—C₄alkyl.

[0117] The term “halogen” includes fluorine, chlorine, bromine andiodine atoms.

[0118] The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further, thesubstitution can be made at any of the groups. For example, substitutedaryl(C₁₋₆)alkyl includes substitution on the aryl group as well assubstitution on the alkyl group.

[0119] The term “oxide” of heteroaryl groups is used in the ordinarywell-known chemical sense and include, for example, N-oxides of nitrogenheteroatoms.

[0120] Compounds described herein may contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention includes all such possible diastereomers as well astheir racemic mixtures, their substantially pure resolved enantiomers,all possible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

[0121] The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acids. Whenthe compound of the present invention is acidic, its corresponding saltcan be conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

[0122] When the compound of the present invention is basic, itscorresponding salt can be conveniently prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include, for example, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

[0123] The pharmaceutical compositions of the present invention comprisea compound represented by Formula I (or pharmaceutically acceptablesalts thereof) as an active ingredient, a pharmaceutically acceptablecarrier and optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

[0124] In practice, the compounds represented by Formula I, orpharmaceutically acceptable salts thereof, of this invention can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound represented by Formula I, or pharmaceutically acceptable saltsthereof, may also be administered by controlled release means and/ordelivery devices. The compositions may be prepared by any of the methodsof pharmacy. In general, such methods include a step of bringing intoassociation the active ingredient with the carrier that constitutes oneor more necessary ingredients. In general, the compositions are preparedby uniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

[0125] Thus, the pharmaceutical compositions of this invention mayinclude a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of Formula I. The compounds of FormulaI, or pharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

[0126] The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

[0127] In preparing the compositions for oral dosage form, anyconvenient pharmaceutical media may be employed. For example, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like may be used to form oral liquid preparations such assuspensions, elixirs and solutions; while carriers such as starches,sugars, microcrystalline cellulose, diluents, granulating agents,lubricants, binders, disintegrating agents, and the like may be used toform oral solid preparations such as powders, capsules and tablets.Because of their ease of administration, tablets and capsules are thepreferred oral dosage units whereby solid pharmaceutical carriers areemployed. Optionally, tablets may be coated by standard aqueous ornonaqueous techniques

[0128] A tablet containing the composition of this invention may beprepared by compression or molding, optionally with one or moreaccessory ingredients or adjuvants. Compressed tablets may be preparedby compressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 1 mg to about 500 mg of the activeingredient and each cachet or capsule preferably containing from about 1to about 500 mg of the active ingredient.

[0129] Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

[0130] Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be. preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol),vegetable oils, and suitable mixtures thereof.

[0131] Pharmaceutical compositions of the present invention can be in aform suitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or pharmaceutically acceptable saltsthereof, via conventional processing methods. As an example, a cream orointment is prepared by mixing hydrophilic material and water, togetherwith about 5 wt % to about 10 wt % of the compound, to produce a creamor ointment having a desired consistency.

[0132] Pharmaceutical compositions of this invention can be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in moulds.

[0133] In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

EXPERIMENTAL PROTOCOLS Assessing the Activity of Selected Compounds toInhibit NR1A/2B NMDA Receptor Activation (FLIPR Assay)

[0134] The activity of selected compounds to inhibit NR1A/2B NMDAreceptor activation measured as NR1A/2B receptor-mediated Ca²⁺ influx isassessed by the following procedure:

[0135] NR1A/2B receptor transfected L(tk) cells are plated in 96-wellformat at 3×10⁶ cells per plate and grown for one—two days in normalgrowth media (Dulbeccos MEM with Na pyruvate, 4500 mg glucose,pen/strep, glutamine, 10% FCS and 0.5 mg/mL geneticin).NR1A/2B-expression in these cells is induced by the addition of 4 nMdexamethasone in the presence of 500 μM ketamine for 16-24 hours. Afterreceptor induction cells are washed using a Labsystem Cellwasher twotimes with assay buffer (Hanks balanced salt solution (BBSS-Mg⁺⁺ free)containing 20 mM HEPES, 0.1% BSA, 2 mM CaCl₂ and 250 μM probenecid). Thecells of each 96 well cell plate are loaded with the Ca⁺⁺ sensitive dyeFluo-3 (Molecular Probes, Inc.) at 4 μM in assay buffer containing 0.5%FBS, and 0.04% pluronic F-127 (Molecular Probes, Inc.) for 1 h at 37° C.avoiding light. The cells are then washed with the Cellwasher four timeswith assay buffer leaving them in 100 μL buffer. Test compounds insolution are pipetted by FLIPR (Fluorometric Imaging Plate Reader) intoeach test well for a 2 min pretreatment. During this time thefluorescence intensity is recorded (excitation at 488 nm and emission at530 nm). The glutamate/glycine 50 μL agonist solution (finalconcentration 1 μM/1 μM) is then added by FLIPR into each well alreadycontaining 150 μL of buffer (containing the test compound or vehicle)and the fluorescence is continuously monitored for 10 min. The endpointfluorescence values are used to determine an IC₅₀ value comparing theagonist-stimulated signal for the vehicle alone sample and that for thecells incubated with each concentration of test compound.

Determining the Apparent Dissociation Constant (Ki) of Compounds forHuman NR1A/NR2B Receptors (Binding Assay)

[0136] The radioligand binding assay is performed at room temperature in96-well microtiter plates with a final assay volume of 1.0 mL in 20 mMHEPES buffer (pH 7.4) containing 150 mM NaCl. Solutions of testcompounds were prepared in DMSO and serially diluted with DMSO to yield20 μL of each of 10 solutions differing by 3-fold in concentration.Non-specific binding (NSB) using hot AMD-1 (10 μM final concentration)and total binding (TB) by using DMSO (2% final concentration). Asolution of NRIA/NR2B receptors (40 pM final concentration) andtritiated AMD-2 (1 nM final concentration) were added to the testcompounds. After 3 h of incubation at room temperature, samples arefiltered through Packard GF/B filters (presoaked in 0.05% PEI,polyethyleninine Sigma P-3143) and washed 10 times with 1 mL of cold 20mM HEPES buffer per wash. After vacuum drying of the filter plates, 40μL of Packard Microscint-20 was added and bound radioactivity determinedin a Packard TopCount. The apparent dissociation constant (Ki), themaximum percentage inhibition (%I_(max)), the minimum percentageinhibition (%I_(min)) and the hill slope (nH) were determined by anon-linear least squares fitting the bound CPM data to Equation #1below. $\begin{matrix}{{{CPM}\quad {Bound}} = {\frac{({SB})\left( {{\% I_{\max}} - {\% I_{\min}}} \right)}{\left( {1 + \left( {\lbrack{Drug}\rbrack/\left( {{{Ki}\left\lbrack {{AMD} - 2} \right\rbrack}/K_{D}} \right)} \right)^{nH}} \right)} + {NSB} + {({SB})\left( {1 - {\% I_{\max}}} \right)}}} & \text{Equation~~~\#1}\end{matrix}$

[0137] where, K_(D) is the apparent dissociation constant for theradioligand for the receptor as determined by hot saturation and SB isthe specifically bound CPM determined from the difference of TB and NSB.

[0138] Compounds AMD-1 and AMD-2 can be synthesized in accordance withthe following general reaction schemes.

[0139] In accordance with scheme 1, hydrogen chloride is bubbled througha solution of the appropriately substituted benzonitrile 1 in methanolat room temperature. The volatiles are removed under reduced pressureand the resulting residue is triturated with ether and filtered to yieldthe desired imidate 2. Imidate 2 is dissolved in methanol at ambienttemperature, treated with amine 3 at ambient temperature and stirredunder argon. The volatiles are removed under reduced pressure and theresidue purified by preparative HPLC or trituration with ether to affordamidine Ia.

[0140] In accordance with scheme 2, at room temperature under argon,amine 3a is dissolved in ether and was treated with 1-M hydrogenchloride in ether (1 equiv.) in a single portion. The resultingprecipitate is stirred vigorously for 10 minutes. The volatiles areremoved under reduced pressure. The residue is suspended in toluene,cooled to 0° C. under argon, treated with 2.0-M trimethylaluminum (1.05equiv.) in a dropwise manner, and stirred for 45 minutes at roomtemperature to afford intermediate 6 (not isolated). Compound 6 is addedto a solution of nitrile 1 in toluene. The reaction is heated to 80° C.without stirring in a sealed tube for 18 h, cooled to ambienttemperature, poured onto a silica gel column and eluted withmethanol/dichloromethane to give the amidine 4.

Preparation of [¹²⁵I]AMD-1

[0141]

[0142] Tritiated AMD-1 was prepared by the following procedure: Amixture of AMD-1, hydrochloride salt, (5 mg, 0.012mmol) in dioxane (0.2mL) containing triethylamine (4 μL) was treated with hexamethylditin (5μL), a catalytic amount of palladium catalyst and heated at 100° C. for45 minutes. The reaction was cooled to room temperature, filteredthrough a glass wool plug, rinsed with methanol and concentrated invacuo to give 10.7 mg of a brown oil. The oil was dissolved in methylenechloride and passed through a small silica column eluting with methylenechloride followed by 5% methanol/methylene chloride. Fractionscontaining the trimethylstannane (Rf 0.26 in 10% methanol/methylenechloride) were pooled and concentrated in vacuo to give thetrimethylstannane as a clear colorless oil. This material was furtherpurified by HPLC (C18 Econosil, 10×250 mm, 20 minute linear gradient,30% MeCN:70% H₂O (0.1% TFA) to 90% MeCN, 3 mL/min, 254 nm, retentiontime 15 minutes) to give the trimethylstannane.

[0143] A Na¹²⁵I shipping vial (10 mCi, Amersham) was charged with a stirbar, an iodobead, 50 μL of methanol and stirred five minutes at roomtemperature. A solution of the trimethylstannane (0.1 mg) in 50 μL ofmethanol containing 5 μL of trifluoroacetic acid was added and thereaction was stirred for five minutes. The reaction was quenched with 50μL of ammonium hydroxide and purified by HPLC (C18 Vydac protein andpeptide column, 4.6×250 mm, 20 minute linear gradient, 30% MeCN:70% H₂O(0.1% TFA) to 90% MeCN, 1 mL/min, retention time 11 minutes). Fractionscontaining the radioactive product were pooled and concentrated in vacuoto give 989 μCi of [¹²⁵I]AMD-1 with a specific activity of 898 Ci/mmolas measured by UV absorbance at 272 nm.

Synthesis of Tritiated AMD-2

[0144] Tritiated AMD-2 was prepared by the following procedure: Thephenol of AMD-2 (2 mg, 0.008 mmol) dissolved in dimethylformamide (0.6mL) and potassium carbonate (1.2 mg) for 1 h. High specific activitytritiated methyl iodide (50 mCi, 0.0006 mmol, in toluene 1 mL, AmericanRadiolabeled Chemicals) was added at room temperature and stirred for 2hours. The reaction mixture was filtered using a Whatman PTFE 0.45 μmsyringeless filter device to remove any insoluble potassium carbonate,washed with Abs. ethanol (2 mL, Pharmco), and the combined filtrateswere concentrated to dryness at room temperature using a rotaryevaporator; this also removed any unreacted tritiated methyl iodide. Theresidue was purified by HPLC chromatography on a Phenomenx Luna C8semi-prep column (Luna 5 micro C8(2), 250×10.0 mm) using a gradientsystem of 20/80 acetonitrile/water with 0.1% trifluoroacetic acid to100% acetonitrile with 0.1% trifluoroacetic acid in 20 min. Totalactivity of the product was 8mCi. Further purification was effected byabsorption onto a Waters C-18 Sep-Pak column (Waters Sep-Pak PLUS C18)and elution with water followed by absolute ethanol. The product wasdiluted with absolute ethanol (10 mL) before submission for finalanalysis.

[0145] The compounds of this invention exhibit IC₅₀'s of less than 50 μMin the FLIPR and binding assays. Thus, the compounds and pharmaceuticalcompositions of this invention have been found to exhibit biologicalactivity as NMDA NR2B antagonists. Advantageously, the IC₅₀'s should beless than 1 μM in the FLIPR and binding assays. Even moreadvantageously, the IC₅₀'s should be less than 0.1 μM in the FLIPR andbinding assays. Accordingly, another aspect of the invention is thetreatment of pain, migraine, depression, anxiety, schizophrenia,Parkinson's disease, or stroke—maladies that are amenable toamelioration through inhibition of NMDA NR2B receptors—by theadministration of an effective amount of the compounds of thisinvention. Further, another aspect of the invention is the treatment ofglaucoma and tinitis—maladies that are also amenable to ameliorationthrough inhibition of NOMA NR2B receptors—by the administration of aneffective amount of the compounds of this invention.

[0146] The abbreviations used herein are as follows unless specifiedotherwise: BH₃*THF Tetrahydrofuran/borane complex BOC t-ButoxycarbonylBOC₂O t-Butoxycarbonyl anhydride CBZ Carbobenyloxy CBZ-Cl Carbobenzylchloride DCM Dichloromethane DIPEA Diisopropylethylamine DMFN,N-Dimethylformamide DMF-DMA Dimethylformamide-Dimethylacetal DMSODimethylsulfoxide EDC 3-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride h hours HOAt 1-Hydroxy-7-azabenzotriazole IPA IsopropanolmCPBA meta Chloroperbenzoic acid min minutes NMR nuclear magneticresonance r.t. or rt room temperature sat. saturated TEA TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran

[0147] The following examples are provided to more fully illustrate thepresent invention, and are not to be construed as limiting the scope ofthe claims in any manner.

EXAMPLES

[0148] The compounds of this invention can be prepared by proceduresshown below.

Intermediates Intermediate 1a Carbonic acid 2,5-dioxo-pyrrolidin-1-ylester 4-methyl-benzyl ester

[0149]

[0150] Disuccinimidyl carbonate (5.03 g, 19.65 mmol) in 30 mL MeCN and30 mL DCM was treated with 4-methylbenzyl alcohol (2.4 g, 19.6 mmol)followed by DMAP (1.20 g, 9.82 mmol). The resulting cloudy reactionmixture was stirred overnight at rt, poured into 100 mL water, andpartitioned. The organic layer was dried over anhydrous sodium sulfateand the solvent evaporated. The solid thus obtained was stirred withapprox. 25 mL ether, filtered, and the resulting product was washed witha small volume of ether and dried.

[0151] Ref: Chem. Pharm. Bull., 38(1):110-115(1990).

[0152] The following compounds were similarly prepared in the mannerdescribed above for INTERMEDIATE 1a:

Intermediate 1b Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester4-chloro-benzyl ester Intermediate 1c Carbonic acid2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester Intermediate 1dCarbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-ethyl-benzyl esterIntermediate 1e Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester4-isopropyl-benzyl ester

[0153] Utilizing the carbonic acid derivatives described above asIntermediates 1a-1e, and following the procedure described below inEXAMPLE 15, step 1, the following INTERMEDIATES 2a-2e were obtained:

Intermediate 2a 4-Methylbenzyl 4-(aminomethyl)piperidine-1-carboxylate

[0154]

Intermediate 2b 4-Chlorobenzyl 4-(aminomethyl)piperidine-1-carboxylateIntermediate 2c 4-Fluorobenzyl 4-(aminomethyl)piperidine-1-carboxylateIntermediate 2d 4-Ethylbenzyl 4-(aminomethyl)piperidine-1-carboxylateIntermediate 2e 4-Isopropylbenzyl4-(aminomethyl)piperidine-1-carboxylate

[0155] The carboxylic acids used in the coupling steps were eithercommercially available or prepared according to the followingreferences: Structure Name Reference

6-Hydroxy-pyridazine-3- carboxylic acid M. Morishita, Chem. Pharm.Bull., 42: 371(1994).

4-Methanesulfonylamino- benzoic acid L. Exner, Collect Czech Chem. Comm,35: 1371-1374(1970).

4-Hydroxy-3-iodo-benzoic acid L. C. King, et al., J. Amer. Chem. Soc.,67: 2089(1945).

3-Fluoro-4-hydroxy- benzoic acid J. Minor et al., J. Org. Chem., (1952),17, 1425.

2-Fluoro-4-hydroxy- benzoic acid G. Gray et al., Mol. Cryst. Liq.Cryst., 67: 1-24(1981).

Thiazole-4-carboxylic acid H. Erlenmeyer et al., Helv. Chim. Acta., 28:362(1945).

2H-Pyrazole-3-carboxylic acid Sokolov et al., J. Gen. Chem. USSR (Eng.)52: 2291(1982).

5-Oxo-4,5-dihydro-1H- [1,2,4]triazole-3-carboxylic acid Gehlen Ann(1952) 577, 237-241.

Thiazole-5-carboxylic acid H. Erlenmeyer et al., Helv. Chim. Acta., 30:1865(1947).

2-Bromo-isonicotinic acid A. Campbell et al., Austral. J. Chem., 24:377(1971).

5-Methyl-3H-imidazole-4- carboxylic acid G. Wellman et al., Synthesis356(1984).

2-Methyl-1H-pyrrole-3- carboxylic acid E. Benary, Chemische Berichte,44: 493(1911).

Oxazole-5-carboxylic acid U.S. Pat. No. 4,785,012

5-Ethyl-2-methyl-2H- pyrazole-3-carboxylic acid H. A. DeWald et al., J.Med. Chem., 16: 1346(1973).

6-Chloro-imidazo[1,2- a]pyridine-2-carboxylic acid WP 96/25414

4-Bromo-thiophene-3- carboxylic acid Tserng, K. et al., J. Org. Chem.,40: 172(1975).

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3-Bromo-isonicotinic acid J. Dejardin et al., Bull. Soc. Chim. Fr.,530(1976).

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3-methyl-3H-imidazole-4- carboxylic acid EP 0306868

Example 1 4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

[0156]

Step 1 Preparation of Benzyl 4-(aminomethyl)piperidine-1-carboxylate

[0157]

[0158] 4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3mL, 368 mmol) in toluene (600 mL) were heated to reflux under dean starkconditions for 2 h. The resulting reaction mixture was cooled to roomtemperature and 500 mL dichloromethane was added. The resulting solutionwas cooled to 5° C. and treated with N-(benzyloxycarbonyloxy)succinimide(91.7 g, 368 mmol). After 10 min, the cooling bath was removed and thereaction mixture stirred for 1 h. The solvents were evaporated and theresulting residue was stirred with 400 mL THF and 400 mL 2 M HCl for 1h. The mixture was concentrated to remove organics and was thenextracted with ether (3×300 mL). The aqueous phase was adjusted to pH14with 50% NaOH and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous sodium sulfate, andthe solvent evaporated to give benzyl4-(aminomethyl)piperidine-1-carboxylate as an oil.

[0159]¹HNMR 500 MHz (δ, CDCl₃) δ7.4-7.2 (m, 5H); 5.12 (s, 2H); 4.20(brs, 2H); 2.77 (brs, 2H); 2.58 (d, J=6.6 Hz, 2H) 1.9-1.7 (m, 2H);1.0-1.5 (m, 5H).

Step 2 Preparation of4-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester

[0160]

[0161] To a mixture of 4-hydroxybenzoic acid (2.5 g, 0.0182 mol),1-hydroxybenzotriazole hydrate (3.33 g, 0.0218 mol), benzyl4-(aminomethyl)piperidine-1-carboxylate (4.5 g, 0.0182 mol) andtriethylamine (3.03 mL, 0.0218 mol) in DMF (30mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.2 g,0.0218 mol) and the mixture allowed to stir at rt for 18 h. The mixturewas quenched into water (200 mL) and extracted with ethyl acetate (200nL). The ethyl acetate extract was washed with 10% aqueous sodiumbicarbonate (100 mL), brine (50 mL), dried over sodium sulfate, andfiltered. The filtrate was concentrated in vacuo and the residuechromatographed on silica using 10-20% acetone/dichloromethane to give6.3 g of 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester as a foam. The foam was dissolved in hot isopropylacetate (125 mL), filtered, and allowed to cool and crystallize. Thereaction volume was reduced in vacuo to 50 mL, allowed to stir overnightat rt and filtered. The resulting solid was dried in vacuo (50° C.)yielding the 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester.

[0162] M.P. 122-123° C. M.S(M+1): 369. ¹H NMR 300 MHz (δ, CDCl₃) δ7.64(d, 2H); 7.4-7.2 (m, 5H); 6.86 (d, 2H); 6.18(m, 1H); 5.85(s, 1H1); 5.15(s, 2H); 4.20 (brs, 2H); 3.35 (brs, 2H); 2.77 (brs, 2H); 1.9-1.7 (m,3H); 1.3-1.1 (m, 2H). Analysis Calcd. for C₂₁H₂₄N₂O4: C, 68.46; H, 6.57;N, 7.60; Found: C, 68.23; H, 6.61; N, 7.48.

[0163] The following compounds were prepared in a manner similar to thatused above for the preparation of4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester, using the appropriate acid in place of the 4-hydroxybenzoic acid.References or experimental procedures are shown for the preparation ofnon-commercially available acids. Appropriately substituted benzyl4-(aminomethyl)piperidine-1-carboxylates were prepared in a similarmanner to that described above in EXAMPLE 1, step 1, with the necessary

[0164] N-(benzyloxycarbonyloxy)succinimides prepared as previouslydescribed (Chem. Pharm Bull 1990, 38(1) 110-115). EX. Name StructureData 2. 4-{[(Pyrazine-2- carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid benzyl ester

M.S(M+1): 370 ¹H NMR 300 MHz(δ, CDCl₃) δ: 12.10(brs, 1H); 8.02(d, 1H,J=2.5 Hz); 7.77(dd, 1H, J=7.7 and 2.5 Hz); 7.4-7.2(m, 5H); 6.59(d, 2H,J=7.7 Hz); 6.12(m, 1H); 5.12(s, 2H); 4.20(brs, 2H); 3.30(brs, 2H);2.77(brs, 2H); 2.0-1.8(m, 3H); 1.3-1.1(m, 2H). 3. 4-{[(3-Amino-pyridine-4-carbonyl)- amino]-methyl}- piperidine-1- carboxylic acidbenzyl ester

M.S(M+1): 369 NMR(300 MHz, CDCl₃) δ: all broad 4. 4-{[(6-Hydroxy-pyridazine-3- carbonyl)-amino]- methyl}-piperidine-1- carboxylic acidbenzyl ester

M.S(M+1): 371 NMR(300 MHz, CDCl₃) δ: 11.55(brs, 1H); 8.04(d, 1H, J=9.8Hz); 7.4-7.1(m, 5H); 7.04(d, 1H, 9.8 Hz); 5.12(s, 2H); 4.22(brs, 2H);3.30(brs, 2H); 2.80(m, 2H); 1.8-1.6(m, 3H); 1.3-1.1(m, 2H) 5. 4-[(4-Methanesulfonylamino- benzoylamino)- methyl]-piperidine-1- carboxylicacid benzyl ester

M.S(M+1): 446 NMR (300 MHz, CDCl₃)) δ: 7.75(d, 2H, J=8.6 Hz); 7.4-7.2(m,5H); 7.25(d, 2H, J=8.6 Hz); 6.95(brs, 1H); 6.25(brs, 1H); 5.12(s, 2H);4.21(brs, 2H); 4.36(brs, 2H); 3.05(s, 3H); 2.78(brs, 2H); 1.9-1.6(m,3H); 1.3-1.1(m, 2H). 6. 4-[(2,4-Dihydroxy- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S(M+1): 385 NMR (300 MHz, CDCl₃)) δ: 12.55(s, 1H); 7.5-7.3(m, 5H);7.22(d, 1H, J=8.6 Hz); 6.41(d, 1H, J=2.5 Hz); 6.34(dd, 1H, J=8.6 and 2.5Hz); 6.22(m, 1H); 5.13(s, 2H); 4.22(brs, 2H); 3.33(brs, 2H); 2.79(brs,2H); 1.8-1.6(m, 3H); 1.3-1.0(m, 2H). 7. 4-[(3,4-Dihydroxy-benzoylamino)- methyl]-piperidine-1- carboxylic acid benzyl ester

M.S(M+1): 385 NMR (300 MHz, CDCl₃)) δ: 7.57(d, 1H, J=1.6 Hz); 7.5-7.3(m,5H); 7.10(dd, 1H, J=8.2 and 1.6Hz); 6.86(d, 1H, J=8.2 Hz); 6.30(m, 1H);5.12(s, 2H); 4.18(brs, 2H); 3.32(brs, 2H); 2.76(brs, 2H); 1.8-1.4(m,3H); 1.3-1.0(m, 2H). 8. 4-[(4-Hydroxy-3- iodo-benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S(M+1): 495 NMR(300 MHz, CDCl₃)) δ: 8.11(d, 1H, J=2.1 Hz); 7.63(dd,1H, J=8.4 and 2.1 Hz); 7.5-7.3(m, 5H); 7.00(d, 1H, J=8.4 Hz); 6.10(m,1H); 5.12(s, 2H); 4.21(brs, 2H); 3.33(brs, 2H); 2.78(brs, 2H);1.8-1.6(m, 3H); 1.3-1.0(m, 2H). 9. 4-[(3-Fluoro-4- hydroxy-benzoylamino)- methyl]-piperidine-1- carboxylic acid benzyl ester

M.S(M+1): 387 NMR(300 MHz, CDCl₃)) δ: 7.56(dd, 1H, J=11.0 and 1.9 Hz);7.5-7.3(m, 6H); 7.03(t, 1H, J=8.4 Hz); 6.16(m, 1H); 5.12(s, 2H);4.20(brs, 2H); 3.33(brs, 2H); 2.78(brs, 2H); 1.9-1.6(m, 3H); 1.3-1.0(m,2H). 10. 4-[(2-Fluoro-4- hydroxy- benzoylamino)- methyl]-piperidine-1-carboxylic acid benzyl ester

M.S(M+1): 387 NMR (300 MHz, CDCl₃)) δ: 7.94(t, 1H, J=9.0 Hz); 7.5-7.2(m,5H); 6.78(m, 1H); 7.73(dd, 1H, J=8.7 and 2.4 Hz); 6.61(dd, 1H, J=13.8and 2.2 Hz); 5.13(s, 2H); 4.20(brs, 2H); 3.37(brs, 2H); 2.78(brs, 2H);1.9-1.6(m, 3H); 1.3-1.0(m, 2H). 11. 4-{[(1H- Benzoimidazole-5-carbonyl)-amino]- methyl}-piperidin-1- carboxylic acid benzyl ester

MS Exact mass: 393.1940. Experimental for C₂₁H₂₄N₄O₃: 393.1921. ¹H NMR(400 MHz, δ, CDCl₃): 8.13-8.11(m, 2H), 7.67(brs, 2H), 7.35-7.28(m, 5H),6.52(d, J=5.98 Hz, 2H), 5.13(s, 2H), 4.21(brs, 2H), 3.39(brs, 2H),2.79(brs, 2H), 1.90-1.78(m, 1H), # 1.78-1.62(m, 2H), 1.29-1.16(m, 2H).12. 4-{[(1H- Benzotriazole-5- carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid benzyl ester

MS Exact mass: 394.1896. Experimental for C₂₁H₂₃N₅O₃: 394.1874. ¹H NMR(400 MHz, δ, CDCl₃): 8.37(s, 1H), 7.78(d, J=8.68 Hz, 2H), 7.66-7.64(m,2H), 7.31-7.22(m, 5H), 6.65(vbs, 2H), 5.09(s, 2H), 4.13(brd, J=11.06,2H), 3.35(brs, 2H), 2.71(brs, 2H), 1.90-1.77(m, # 1H), 1.71(brd,J=11.61Hz, 2H), 1.26-1.12(m, 2H). 13. 4-[(4-Cyano- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

¹H NMR(δ, CDCl₃): 7.86(d, J=8.05 Hz, 2H), 7.74(d, J=8.05 Hz, 2H),7.25-7.4(m, 5H), 6.31(brt, J=5.61 Hz, 1H), 5.12(s, 2H), 4.22(brs, 2H),3.37(brs, 2H), 2.79(brs, 2H), 1.7-1.9(m, 3H), 1.23(m, 2H). 14.4-{[(6-Hydroxy- pyridine-3-carbonyl)- amino]-methyl}- piperidine-1-carboxylic acid 4- methyl-benzyl ester

M.S(M+1): 384 NMR(300 MHz, CDCl₃) δ: 12.20(brs, 1H); 8.02(d, 1H, J=2.5Hz); 7.75(dd, 1H, J=9.6 and 2.5 Hz); 7.24(d, 2H, J=7.9 Hz); 7.15(d, 2H,J=7.9 Hz); 6.56(d, 1H, J=9.6 Hz); 6.20(m, 1H); 5.07(s, 2H); 4.20(brs,2H); 3.30(brs, 2H); 2.35(brs, 2H); 1.8-1.6(m, 3H); 1.3-1.1(m, 2H). 15.4-{[(6-Hydroxy- pyridazine-3- carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid 4- methyl-benzyl ester

M.S(M+1): 385 NMR(300 MHz, CDCl₃)) δ: 11.9(s, 1H); 8.05(d, 1H, J=9.9Hz); 7.25(d, 2H, J=7.9 Hz); 7.16(d, 2H, J=7.9 Hz); 7.04(d, 1H, J=9.9Hz); 5.08(s, 2H); 4.20(brs, 2H); 3.32(brs, 2H); 2.76(m, 2H); 2.35(s,3H); 1.8-1.6(m, 3H); 1.3-1.1(m, 2H). 16. 4-{[(6-Hydroxy-pyridine-3-carbonyl)- amino]-methyl}- piperidine-1- carboxylic acid 4-fluoro-benzyl ester

M.S(M+1): 388 NMR(300 MHz, CDCl₃)) δ: 12.2(s, 1H); 8.03(d, 1H, J=2.6Hz); 7.77(dd, 1H, J=9.6 and 2.6 Hz); 7.34(m, 2H); 7.03(t, 2H, J=8.6 Hz);6.57(d, 1H, J=9.6 Hz); 5.07(s, 2H); 4.20(brs, 2H); 3.31(brs, 2H);2.76(brs, 2H); 2.35(s, 3H); 1.8-1.6(m, 3H); 1.3-1.1(m, 2H). 17.4-{[(6-Hydroxy- pyridine-3-carbonyl)- amino]-methyl}- piperidine-1-carboxylic acid 4- chloro-benzyl ester

M.S(M+1): 404 NMR(300 MHz, CDCl₃)) δ: 11.8(brs, 1H); 8.02(d, 1H, J=2.4Hz); 7.74(dd, 1H, J=9.6 and 2.4 Hz); 7.4-7.2(m, 4H); 6.58(d, 1H, J=9.6Hz); 6.03(m, 1H); 5.08(s, 2H); 4.20(brs, 2H); 3.31(brs, 2H); 2.78(brs,2H); 1.8-1.4(m, 3H); 1.3-1.1(m, 2H). 18. 4-{[(6-Hydroxy-pyridine-3-carbonyl)- amino]-methyl}- piperidine-1- carboxylic acidindan-2-yl ester

M.S(M+1): 396 NMR(300 MHz, CDCl₃)) δ: 12.0(brs, 1H); 8.01(d, 1H, J=2.5Hz); 7.74(dd, 1H, J=9.6 and 2.5 Hz); 7.3-7.1(m, 4H); 6.57(d, 1H, J=9.6Hz); 6.04(m, 1H); 5.46(m, 1H); 4.3-4.1(m, 2H); 3.32(m, 4H); 3.04(d, 1H,J=3.2 Hz); 3.00(d, 1H, J=3.2Hz); 2.72(m, 2H); 1.8-1.6(m, 3H); 1.3-1.0(m,# 2H). 19. 4-[(4-Hydroxy- benzoylamino)- methyl]-piperidine-1-carboxylic acid 4- fluoro-benzyl ester

M.S(M+1): 387 NMR (300 MHz, CDCl₃)) δ: 7.65(d, 2H, J=8.6 Hz); 7.33(m,2H); 7.03(t, 2H, J=8.6 Hz); 6.86(d, 2H, J=8.6 Hz); 6.64(s, 1H); 6.22(m,1H); 5.08(s, 2H); 4.14(brs, 2H); 3.33(brs, 2H); 2.67(brs, 2H);1.8-1.6(m, 3H); 1.3-1.0(m, 2H). 20. 4-[(4-Hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylic acid 4- chloro-benzyl ester

M.S(M+1): 403 NMR(300 MHz, CDCl₃)) δ: 7.66(d, 2H, J=8.6 Hz); 7.30(m,4H); 6.86(d, 2H, J=8.6 Hz); 6.33(s, 1H); 6.22(m, 1H); 5.08(s, 2H);4.14(brs, 2H); 3.33(brs, 2H); 2.77(brs, 2H); 1.8-1.6(m, 3H); 1.3-1.0(m,2H). 21. 4-[(4-Hydroxy- benzoylamino)- methyl]-piperidine-1- carboxylicacid indan-2-yl ester

M.S(M+1): 395 NMR (300 MHz, CDCl₃)) δ: 7.63(d, 2H, J=8.6 Hz); 7.3-7.1(m,4H); 6.85(d, 2H, J=8.6 Hz); 6.27(m, 1H); 5.46(m, 1H); 4.3-3.8(m, 2H);3.3(dd, 4H, J=16.9 and 6.6 Hz); 3.0(dd, 2H, J=7.0 and 3.2 Hz); 2.69(dt,2H, J=13.2 and 2.7 Hz); 1.8-1.6(m, 3H); 1.3-1.0(m, 2H). 22.4-[(4-Hydroxy- benzoylamino)- methyl]-piperidine-1- carboxylic acid 4-methyl-benzyl ester

M.S(M+1): 383 NMR(300 MHz, CDCl₃)) δ: 7.64(d, 2H, J=8.8 Hz); 7.24(d, 1H,J=8.0 Hz); 7.15(d, 1H, J=8.0 Hz); 6.86(d, 2H, J=8.8 Hz); 6.24(m, 1H);5.08(s, 2H); 4.18(brs, 2H); 3.32(brs, 2H); 2.75(brs, 2H); 2.34(s, 3H);1.8-1.6(m, 3H); 1.3-1.0(m, 2H). 23. 4-{[(Pyridine-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- methyl-benzyl ester

¹H NMR(δ, CDCl₃): 8.75(d, J=5.86Hz, 2H), 7.60(d, J=4.89 Hz, 2H), 7.25(d,J=8.05 Hz, 2H), 7.16(d, J=8.05 Hz, 2H), 6.32(brt, 1H), 5.08(s, 2H),4.22(brs, 2H), 3.37(brs, 2H), 2.77(brs, 2H), 2.35(s, 3H), 1.7-1.9(m,3H), 1.21(m, 2H). 24. 4-{[(Pyridine-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- chloro-benzyl ester

¹H NMR (δ, CDCl₃): 8.75(d, J=4.64 Hz, 2H), 7.60(d, J=5.13 Hz, 2H),7.32(d, J=8.05 Hz, 2H), 7.28(d, J=8.55 Hz, 2H), 6.35(brt, 1H), 5.08(s,2H), 4.22(brd, 2H), 3.37(brd, 2H), 2.79(brs, 2H), 1.7-1.9(m, 3H),1.23(m, 2H). 25. 4-{[(Pyridine-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- fluoro-benzyl ester

¹H NMR (δ, CDCl₃): 8.75(d, J=5.61 Hz, 2H), 7.60(d, J=6.11 Hz, 2H),7.28(dd, J=5.62, 8.3 Hz, 2H), 7.04(t, J=8.8 Hz, 2H), 6.33(brt, 1H),5.08(s, 2H), 4.23(brd, 2H), 3.38(brd, 2H), 2.78(brs, 2H), 1.7-1.9(m,3H), 1.22(m, 2H). 26. 4-[(4-Hydroxy-3- methyl- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

¹H NMR (δ, CDCl₃): 7.56(brs, 1H), 7.49(dd, J=2.2, 8.3 Hz, 1H),7.25-7.4(m, 5H), 6.79(d, J=8.3 Hz, 1H), 6.13(brt, 1H), 5.55(s, 1H),5.12(s, 2H), 4.22(brs, 2H), 3.33(brs, 2H), 2.78(brs, 2H), 2.28(s, 3H),1.7-1.9(m, 3H), 1.23(m, 2H). 27. 4-[(3-Chloro-4- hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

¹H NMR (δ, CDCl₃): 7.80(d, J=2.2 Hz, 1H), 7.57(dd, J=2.2, 8.55 Hz, 1H),7.25-7.4(m, 5H), 7.05(d, J=8.55 Hz, 1H), 6.13(brt, 1H), 6.04(brs, 1H),5.12(s, 2H), 4.22(brs, 2H), 3.33(brs, 2H), 2.78(brs, 2H), 1.7-1.9(m,3H), 1.23(m, 2H). 28. 4-{[(Thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester ¹H NMR (δ, CDCl₃):7.84(s, 1H), 7.41-7.27(m, 7H), 6.24(brt, 1H), 5.06(s, 2H), 4.19(brd,2H), 3.30(brs, 2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.18(m, 2H). 29.4-{[(Thiazole-4- carbonyl)-amino]- methyl}-piperidine-1- carboxylic acidbenzyl ester

¹H NMR (δ, CDCl₃): 8.74(d, 1H), 8.17(d, 1H), 7.50(brt, 1H), 7.26(m, 5H),5.11(s, 2H), 4.19(brs, 2H), 3.35(brs, 2H), 2.78(brt, 2H), 1.9-1.7(m,3H), 1.21(m, 2H). 30. 4-{[(2H-Pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

¹H NMR (δ, CDCl₃): 7.59(d, J=1.3 Hz, 1H), 7.36-7.28(m, 5H), 7.07(brt,1H), 6.82(d, J=1.3 Hz, 1H), 5.13(s, 2H), 4.20(brs, 2H), 3.37(brs, 2H),2.78(brt, 2H), 1.9-1.7(m, 3H), 1.21(m, 2H). 31. 4-{[(5-Oxo-4,5-dihydro-1H- [1,2,4]triazole-3- carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid benzyl ester

¹H NMR (500 MHz, δ, CDCl₃): 11.55(s, br, 2H), 7.45-7.30(m, 6H), 5.12(s,2H), 4.19(s, 2H), 3.25(m, 2H), 2.75(m, 2H), 1.85-1.65(m, 3H), 1.15(m,2H). 32. 4-{[(2H- [1,2,4]Triazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

¹H NMR (500 MHz, δ, DMSO-d₆): 14.60(s, br, 1H), 8.80-8.30(s, br, 2H),7.40-7.30(m, 5H), 5.07(s, 2H), 3.98(d, 2H), 3.15(t, 2H), 2.77(m, br,2H), 1.77(m, 1H), 1.63(d, 2H), 1.05(m, 2H). 33. 4-{[(Thiazole-5-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

¹H NMR (500 MHz, δ, DMSO-d₆): 9.21(s, 1H), 8.74(m, 1H), 8.46(s, 1H),7.40-7.28(m, 5H), 5.09(s, 2H), 4.00(d, 2H), 3.12(t, 2H), 2.90-2.70(m,br, 2H), 1.80-1.65(m, 3H), 1.05(m, 2H). 34. 4-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

¹H NMR (500 MHz, δ, CD₃OD): 8.2-7.8(s, br, 2H), 7.36-7.25(m, 5H),5.11(s, 2H), 4.15(m, 2H), 3.23(m, 2H), 2.90-2.75(s, br, 2H),1.90-1.70(m, 3H), 1.20-1.10(m, 2H). 35. 4-{[(2-Bromo-pyridine-4-carbonyl)- amino]-methyl}- piperidine-1- carboxylic acidbenzyl ester

¹H NMR (500 MHz, δ, DMSO-d₆): 8.88(m, 1H), 8.54(d, 1H), 7.99(s, 1H),7.78(d, 1H), 7.38-7.28(m, 5H), 5.07(s, 1H), 4.00(d, 2H), 3.16(t, 2H),2.90-2.70(m, 2H), 1.80-1.65(m, 3H), 1.09(m, 2H). 36. 4-{[(1H-Pyrrole-2-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

¹H NNR (δ, CDCl₃): 9.55(brs, 1H), 7.39-7.28(m, 5H), 6.92(m, 1H), 6.57(m,1H), 6.22(m, 1H), 6.01(brt, 1H), 5.08(s, 2H), 4.20(brs, 2H), 3.28(brs,2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.21(m, 2H). 37.4-{[(1H-Imidazole-4- carbonyl)-amino]- methyl}-piperidine-1- carboxylicacid benzyl ester

¹H NMR (δ, CDCl₃): 7.58(m, 2H), 7.38-7.27(m, 5H), 5.10(s, 2H), 4.20(brd,2H), 3.37(brs, 2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.21(m, 2H). 38.4-{[(1-Methyl-1H- pyrrole-2-carbonyl)- amino]-methyl}- piperidine-1-carboxylic acid benzyl ester

¹H NMR (δ, CDCl₃): 7.38-7.25(m, 5H), 6.71(m, 1H), 6.50(m, 1H), 6.08(m,1H), 6.00(brt, 1H), 5.11(s, 2H), 4.22(brs, 2H), 3.94(s, 3H), 3.26(brs,2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.21(m, 2H). 39. 4-{[(5-Methyl-3H-imidazole-4- carbonyl)-amino]- methyl}-piperidine-1- carboxylic acidbenzyl ester

¹H NMR (δ, CDCl₃): 9.62(brs, 1H), 7.40(s, 1H), 7.31(m, 6H), 5.12(s, 2H),4.19(brd, 2H), 3.25(brs, 2H), 2.77(brt, 2H), 2.59(s, 3H), 1.9-1.7(m,3H), 1.21(m, 2H). 40. 4-{[(1H-Pyrrole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

¹H NMR (δ, CDCl₃): 8.55(brs, 1H), 7.28(m, 6H), 6.78(s, 1H), 6.40(s, 1H),5.88(brt, 1H), 5.10(s, 2H), 4.19(brs, 2H), 3.30(brs, 2H), 2.77(brt, 2H),1.9-1.7(m, 3H), 1.20(m, 2H). 41. 4-{[(Thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- methyl-benzyl ester

¹H NMR (δ, CDCl₃): 7.83(m, 1H), 7.38(m, 2H), 7.24(d, 2H), 7.18(d, 2H),6.19(brt, 1H), 5.02(s, 2H), 4.20(brs, 2H), 3.30(brs, 2H), 2.77(brt, 2H),2.35(s, 3H), 1.9-1.7(m, 3H), 1.21(m, 2H). 42. 4-{[(2H-Pyrazole-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4- fluoro-benzylester

¹H NMR (δ, CDCl₃): 7.60(d, 1H), 7.30(d, 2H), 7.04(m, 3H), 6.82(d, 1H),5.04(s, 2H), 4.18(brs, 2H), 3.33(brs, 2H), 2.77(brt, 2H), 1.9-1.7(m,3H), 1.21(m, 2H). 43. 4-{[(2H-Pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- chloro-benzyl ester

¹H NMR (δ, CDCl₃): 7.58(d, 1H), 7.27(m, 4H), 7.04(brt, 1H), 6.82(d, 1H),5.05(s, 2H), 4.18(brs, 2H), 3.36(brs, 2H), 2.77(brt, 2H), 1.9-1.7(m,3H), 1.21(m, 2H). 44. 4-{[(2H-Pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- methyl-benzyl ester

¹H NMR (δ, CDCl₃): 7.60(d, 1H), 7.22(d, 2H), 7.17 d, 2H), 6.97(brt, 1H),6.84(d, 1H),, 5.04(s, 2H), 4.20(brs, 2H), 3.35(brs, 2H), 2.77(brt, 2H),2.37(m, 3H), 1.9-1.7(m, 3H), 1.21(m, 2H). 45. 4-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4- fluoro-benzylester

¹H NMR (δ, CDCl₃): 7.94(s, 2H), 7.30(m, 2H), 7.01(m, 2H), 6.60(brs, 1H),5.03(s, 2H), 4.16(brd, 2H), 3.24(brs, 2H), 2.75(brs, 2H), 1.9-1.7(m,3H), 1.15(m, 2H). 46. 4-{[(1H-Pyrazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- chloro-benzyl ester

¹H NMR (δ, CDCl₃): 7.94(s, 2H), 7.26(m, 4H), 6.43(brs, 1H), 5.03(s, 2H),4.17(brs, 2H), 3.25(brs, 2H), 2.77(brs, 2H), 1.9-1.7(m, 3H), 1.15(m,2H). 47. 4-{[(1H-Pyrazole-4- carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid 4- methyl-benzyl ester

¹H NMR (δ, CDCl₃): 7.94(s, 2H), 7.25(d, 2H), 7.16(d, 2H), 6.03(brt, 1H),5.06(s, 2H), 4.20(brs, 2H), 3.30(brs, 2H), 2.77(brt, 2H), 2.37(s, 3H),1.9-1.7(m, 3H), 1.20(m, 2H). 48. 4-{[(1H-Pyrazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid indan-2-yl ester

¹H NMR (δ, CDCl₃): 7.94(s, 2H), 7.20(m, 4H), 6.15(brt, 1H), 5.42(m, 1H),4.10(brd, 2H), 3.30(m, 4H), 3.00(dd, 2H), 2.70(t, 2H), 1.8-1.6(m, 3H),1.18(m, 2H). 49. 4-{[(1H-Pyrrole-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- methyl-benzyl ester

¹H NMR (δ, CDCl₃): 9.43(brs, 1H), 7.24(d, 2H), 7.17(d, 2H), 6.91(s, 1H),6.55(s, 1H), 6.22(m, 1H), 5.95(brt, 1H), 5.06(s, 2H), 4.19(brs, 2H),3.30(brs, 2H), 2.77(brt, 2H), 2.36(s, 3H), 1.9-1.7(m, 3H), 1.18(m, 2H).

[0165] EX. Name Structure Data 50. 4-{[(1H-Imidazole-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4- chloro-benzylester

¹H NMR(δ, CDCl₃): 7.59(s, 2H), 7.30(m, 5H), 5.06(s, 2H), 4.18(brs, 2H),3.33 (brs, 2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.21(m, 2H). 51.4-{[(1-Methyl-1H- pyrrole-2-carbonyl)- amino]-methyl}- piperidine-1-carboxylic acid 4- fluoro-benzyl ester

¹H NMR(δ, CDCl₃): 7.31(dd, 2H), 7.02 (dd, 2H), 6.72(s, 1H), 6.50(m, 1H),6.08(m, 1H), 6.00 (brt, 1H), 5.04(s, 2H), 4.18(brs, 2H), 3.93(s, 3H),3.25 (brs, 2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.18(m, 2H). 52.4-{[(1H-Pyrrole-2- carbonyl)-amino]- methyl}-piperidine-1- carboxylicacid 4- chloro-benzyl ester

¹H NMR(δ, CDCl₃): 9.37(brs, 1H), 7.24 (m, 4H), 6.92(s, 1H), 6.53(s, 1H),6.22(m, 1H), 5.93(brt, 1H), 5.06(s, 2H), 4.20 (brs, 2H), 3.31(brs, 2H),2.77(brt, 2H), 1.9-1.7(m, 3H), 1.18 (m, 2H). 53. 4-{[(2-Methyl-1H-pyrrole-3-carbonyl)- amino]-methyl}- piperidine-1- carboxylic acid 4-methyl-benzyl ester

¹H NMR(δ, CDCl₃): 8.10(brs, 1H), 7.25 (d, 2H), 7.17(d, 2H), 6.59(m, 1H),6.23 (m, 1H), 5.81(brt, 1H), 5.06(s, 2H), 4.20(brs, 2H), 3.26 (brs, 2H),2.77(brt, 2H), 2.55(s, 3H), 2.36(s, 3H), 1.9-1.7 (m, 3H), 1.20(m, 2H).54. 4-{[(1H-Pyrrole-3- carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid 4- methyl-benzyl ester

¹H NMR(δ, CDCl₃): 8.55(brs, 1H), 7.36 (m, 1H), 7.25(d, 2H), 7.17(d, 2H),6.77(m, 1H), 6.40(m, 1H), 5.86(brt, 1H), 5.06 (s, 2H), 4.19(brs, 2H),3.29(brs, 2H), 2.77(brt, 2H), 2.36(s, 3H), 1.9-1.7(m, 3H), 1.18(m, 2H).55. 4-{[(Thiazole-5- carbonyl)-amino]- methyl}-piperidine-1- carboxylicacid 4- methyl-benzyl ester

¹H NMR(δ, CDCl₃): 8.90(s, 1H), 8.24(s, 1H), 7.24(d, 2H), 7.16(d, 2H),6.24 (brt, 1H), 5.05(s, 2H), 4.20(brs, 2H), 3.35(brs, 2H), 2.77 (brt,2H), 2.36(s, 3H), 1.9-1.7(m, 3H), 1.21(m, 2H). 56. 4-{[(Oxazole-5-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4- methyl-benzylester

¹H NMR(δ, CDCl₃): 7.90(s, 1H), 7.72(s, 1H), 7.23(d, 2H), 7.17(d, 2H),6.35 (brt, 1H), 5.05(s, 2H), 4.20(brs, 2H), 3.33(brs, 2H), 2.77 (brt,2H), 2.35(s, 3H), 1.9-1.7(m, 3H), 1.20(m, 2H). 57. 4-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4-isopropyl-benzyl ester

¹H NMR(δ, CDCl₃): 7.93(s, 2H), 7.25(m, 4H), 6.62(brt, 1H), 5.07(s, 2H),4.16 (brd, 2H), 3.26(brs, 2H), 2.89(m, 1H), 2.71(brt, 2H), 1.9-1.7 (m,3H), 1.23(d, 6H), 1.18(m, 2H). 58. 4-{[(1H-Pyrazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid thiophen-3-ylmethyl ester

¹H NMR(δ, CDCl₃): 10.50(brs, 1H), 7.94 (s, 2H), 7.28(m, 2H), 7.08(m,1H), 5.93 (brt, 1H), 5.11(s, 2H), 4.19(brs, 2H), 3.31(brs, 2H), 2.77(brt, 2H), 1.9-1.7(m, 3H), 1.19(m, 2H). 59. 4-[(4-Hydroxy-benzoylamino)- methyl]-piperidine-1- carboxylic acid 4- isopropyl-benzylester

¹H NMR(δ, CD₃OD): 8.24(brd, 1H) 7.68(d, 2H), 7.20(m, 4H), 6.79(d, 2H),5.02(s, 2H), 4.10(d, 2H), 3.20(t, 2H), 2.81(m, 1H), 2.77(brs, 2H), 1.77(m, 1H), 1.70(brd, 2H), 1.20(d, 6H), 1.16(m, 2H). 60. 4-[(4-Hydroxy-benzoylamino)- methyl]-piperidine-1- carboxylic acid thiophen-3-ylmethylester

¹H NMR(δ, CDCl₃): 7.94(s, 2H), 7.26(m, 4H), 7.09(d, 1H), 5.92(brt, 1H),5.14 (s, 2H), 4.19(brs, 2H), 3.30(brs, 2H), 2.77(brt, 2H), 1.9-1.7 (m,3H), 1.20(m, 2H). 61. 4-{[(Pyridine-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- isopropyl-benzyl ester

¹H NMR(δ, CDCl₃): 8.72(d, 2H), 7.60(d, 2H), 7.22(m, 4H), 6.55(brt, 1H),5.06 (s, 2H), 4.21(brd, 2H), 3.33(brs, 2H), 2.90(m, 1H), 2.77 (brt, 2H),1.9-1.7(m, 3H), 1.21(d, 6H), 1.18(m, 2H). 62. 4-{[(2H-Pyrazole-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4-isopropyl-benzyl ester

¹H NMR(δ, CDCl₃): 7.57(m, 1H), 7.23 (m, 4H), 7.02(brt, 1H), 6.83(m, 1H),5.06(s, 2H), 4.19 (brs, 2H), 3.33(brs, 2H), 2.90(m, 1H), 2,77(brt, 2H),1.9-1.7 (m, 3H), 1.21(d, 6H), 1.18(m, 2H). 63. 4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid 4-isopropyl-benzyl ester

¹H NMR(δ, CDCl₃): 9.79(brs, 1H), 7.30-7.15(m, 5H), 6.70(s, 1H), 6.42(s,1H), 6.30(brt, 1H), 5.06 (s, 2H), 4.17(brs, 2H), 3.25(brs, 2H), 2.90(m,1H), 2.75 (brs, 2H), 1.9-1.7(m, 3H), 1.22(d, 6H), 1.17(m, 2H). 64.4-Hydroxy-N-[1-(3- phenyl-propionyl)- piperidin-4- ylmethyl]-benzamide

¹H NMR(δ, CDCl₃): 8.80(brs, 1H), 7.63 (d, 2H), 7.3-7.1(m, 5H), 6.89(d,2H), 6.69(brt, 1H), 4.58 (d, 1H), 3.76(d, 1H), 3.35-3.18(m, 2H), 2.90(m,3H), 2.60(t, 2H), 2.49(t, 1H), 1.9-1.7(m, 3H), 1.1-0.9 (m, 2H). 65.4-{[(2-Chloro- pyridine-4-carbonyl)- amino]-methyl}- piperidine-1-carboxylic acid benzyl ester

M.S. (M⁺ + 1) 388 66. 4-{[(6-Amino- pyridine-3-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 369 67. 4-(Benzoylamino- methyl)-piperidine-1- carboxylicacid benzyl ester

M.S. (M⁺ + 1) 353 68. 4-[(3-Cyano- benzoylamino)- methyl]-piperidine-1-carboxylic acid benzyl ester

M.S. (M⁺ + 1) 378 69. 4-{[(Pyridine-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid indan-2-yl ester

M.S. (M⁺ + 1) 380 70. 4-{[(2-Amino- pyridine-3-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 369 71. 4-[(4-Methylamino- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 382 72. 4-[(4-Amino- benzoylamino)- methyl]-piperidine-1-carboxylic acid benzyl ester

M.S. (M⁺ + 1) 368 73. 4-[(4- Trifluoromethoxy- benzolyamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 437 74. 4-[(4-Fluoro- benzoylamino)- methyl]-piperidine-1-carboxylic acid benzyl ester

M.S. (M⁺ + 1) 371 75. 4-[(2-Amino- benzoylamino)- methyl]-piperidine-1-carboxylic acid benzyl ester

M.S. (M⁺ + 1) 368 76. 4-{[(5-Ethyl-2- methyl-2H-pyrazole-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 385 77. 4-{[(6-Chloro- imidazo[1,2- a]pyridine-2-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 427 78. 4-{[(4-Bromo- thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 438 79. 4-{[(Isoxazole-5- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 344 80. 4-{[(1H-Imidazole-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 343 81. 4-{[(3-Bromo- pyridine-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 433 82. 4-{[([1,6]- Naphthyridine-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 405 83. 4-{[(1-Methyl-1H- imidazole-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 357 84. 4-{[(5-Bromo- pyridine-3-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 432 85. 4-{[(Isoxazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 344 86. 4-{[(6-Bromo- pyridine-3-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 432 87. 4-{[(2-Methyl- thiazole-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 374 88. 4-{[(Oxazole-5- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 344 89. 4-{[(Pyrimidine-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 355 90. 4-{[(1,4,5,6- Tetrahydro- cyclopentapyrazole-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 383 91. 4-{[(2- Methylsulfanyl- thiazole-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 406 92. 4-{[(5-Methyl- thiazole-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 374 93. 4-{[(5-Methyl-2H- [1,2,4]triazole-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 358 94. 4-{[(4-Phenyl- thiazole-2-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 436 95. 4-{[(5- Hydroxymethyl-3H- imidazole-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 373 96. 4-{[(2-Methyl- thiazole-5-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 374 97. 4-{[(2-Methyl-1H- pyrrole-3-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 356 98. 4-{[(2-Methyl- thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 373 99. 4-{[(Thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- fluoro-benzyl ester

M.S. (M⁺ + 1) 377 100. 4-{[(Thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- chloro-benzyl ester

M.S. (M⁺ + 1) 393 101. 4-{[(Thiophene-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid indan-2-yl ester

M.S. (M⁺ + 1) 385 102. 4-{[(2H-Pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid indan-2-yl ester

M.S. (M⁺ + 1) 369 103. 4-{[(1H-Imidazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- methyl-benzyl ester

M.S. (M⁺ + 1) 357 104. 4-{[(1-Methyl-1H- pyrrole-2-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid 4- methyl-benzyl ester

M.S. (M⁺ + 1) 370 105. 4-{[(1H-Imidazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- fluoro-benzyl ester

M.S. (M⁺ + 1) 361 106. 4-{[(1H-Imidazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid indan-2-yl ester

M.S. (M⁺ + 1) 369 107. 4-{[(1-Methyl-1H- pyrrole-2-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid 4- chloro-benzyl ester

M.S. (M⁺ + 1) 390 108. 4-{[(1-Methyl-1H- pyrrole-2-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid indan-2-yl ester

M.S. (M⁺ + 1) 382 109. 4-{[(1H-Pyrrole-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- fluoro-benzyl ester

M.S. (M⁺ + 1) 360 110. 4-{[(1H-Pyrrole-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid indan-2-yl ester

M.S. (M⁺ + 1) 368 111. 4-{[(1H-Pyrazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- bromo-thiophen-3- ylmethylester

M.S. (M⁺ + 1) 427 112. 4-{[(Pyrazine-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 355 113. 4-{[(Quinoline-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 404 114. 4-{[(2,6-Dihydroxy- pyridine-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 386 115. 4-{[(1-Oxy-pyridine- 4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 370 116. 4-{[(Pyrimidine-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 355 117. 4-{[(1-Methyl-1H- pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 357 118. 4-{[(2-Methyl-2H- pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 357 119. 4-{[(1-Methyl-1H- pyrazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 357 120. 4-{[([1,2,5]- Thiadiazole- 3-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 361 121. 4-{[(5-Bromo- pyridine-2-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 432 122. 4-{[(Pyrimidine-5- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 355 123. 4-{[(Pyrazolo[1,5-a]- pyrimidine-3-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 394 124. 4-{[(6-Bromo- pyridine-2-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 432 125. 4-{[(Benzothiazole-2- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 410 126. 4-{[(3,5-Dimethyl- 1H-pyrrole-2-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 370 127. 4-{[(3-Methyl- pyridine-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 368 128. 4-{[(6-Cyano- pyridine-3-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 379 129. 4-{[(2-Methyl- pyridine-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 368 130. 4-{[(2-Methoxy-6- methyl-pyridine-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 398 131. 4-{[(2-Chloro-6- methyl-pyridine-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 402 132. 4-{[(6-Amino- pyridazine-3- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 370 133. 4-[(2-Hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 369 134. 4-[(3-Hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 369 135. 4-[(2,5-Dihydroxy- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 385 136. 4-[(4-Hydroxy-3,5- diiodo- benzoylamino)-methyl]-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 621

Example 137 1H-Pyrazole-4-carboxylic acid[1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

[0166]

Step 1 1H-Pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide

[0167]

[0168]4-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acidbenzyl ester (EXAMPLE 34) (600 mg, 1.75 mmol), 10% palladium on Carbon(150 mg) and ethanol (15 nL) were combined in a Parr® jar andhydrogenated at 50 psi for 24 h. The reaction mixture was filteredthrough Celite® and the filtrate was evaporated in vacuo to give theproduct as a white foam.

Step 2 1H-Pyrazole-4-carboxylic acid[1-(3-phenyl-propionyl)-piperidin-4-ylmethyl]-amide

[0169]

[0170] 1H-Pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide (352mg, 1.69 mmol), hydrocinnamoyl chloride (503 μL, 3.38 mmol),diisopropylethylamine (294 μL, 1.69 mmol) and DMF (4 mL) were combinedunder Nitrogen and stirred at 25° C. for 24 h. Sodium hydroxide (1 mL,2N) was added and the mixture was stirred 1 h. Water was added and thecontents of the reaction flask were extracted with EtOAc (3×50 mL). Thecombined organic extracts were dried with Na₂SO₄ and filtered. Thefiltrate was removed in vacuo and the remaining residue was purifiedusing an ISCO® normal phase silica chromatography system (CH₂Cl₂ (100%)to CH₂Cl₂:MeOH:NH₄OH 90:10:1). Fractions containing the desired productwere combined and the solvent was removed in vacuo to give a colorlessoil. Addition of EtOAc followed by IN HCl/EO gave the product as a whitesolid.

[0171]¹H NMR (500 MHz, δ, DMSO-d₆): 8.10 (m, 1H), 8.04 (s, 2H),7.28-7.20 (m, 4H), 7.18-7.14 (m, 1H), 4.38 (m, 1H), 3.85 (m, 1H), 3.06(m, 2H), 2.90 (m, 1H), 2.80 (t, 2H), 2,60 (m, 2H), 1.75-1.60 (m, 4H),0.95 (m, 2H).

[0172] The following compounds were prepared by substituting theappropriate acid chloride for the hydrocinnamoyl chloride in the aboveprocedure. EX. Name Structure Analytical Data 138 1H-Pyrazole-4-carboxylic acid [1-(2- phenyl-cyclopropane- carbonyl)-piperidin-4-ylmethyl]-amide

¹H NMR(500MHz, δ, DMSO-d₆): 8.08-7.98(m, 3H), 7.26 (m, 2H), 7.17(m, 3H),4.38(m, 1H), 4.16(m, 1H), 3.15-2.97(m, 3H), 2.58 (m, 1H), 2.26(m, 2H),1.80-1.60(m, 3H), 1.30(m, 1H), 1.20-0.95(m, 3H). 139 1H-Pyrazole-4-carboxylic acid [1-(3- phenyl-acryloyl)- piperidin-4-ylmethyl]- amide

¹H NMR(500MHz, δ, DMSO-d₆): 8.16 (s, br, 1H), 8.07(m, 1H), 7.88(s, br,1H), 7.70(m, 2H), 7.48-7.34(m, 4H), 7.26 (m, 2H), 4.48(m, 1H), 4.29(m,1H), 3.17-3.00(m, 3H), 2.65(m, 1H), 1.85-1.69(m, 3H), 1.15-1.00(m, 2H).

[0173] The following examples were prepared from 1H-pyrazole4-carboxylicacid (piperidin-4-ylmethyl)-amide as described in Example 1 Step 2. EX.Name Structure Analytical Data 140 [1-Benzyl-2-oxo-2-(4-{[(1H-pyrazole-4- carbonyl)-amino]- methyl}-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester

M.S. (M⁺ + 1) 456 141 [1-(4-Chloro-benzyl)- 2-oxo-2-(4-{[(1H-pyrazole-4-carbonyl)- amino]-methyl}- piperidin-1-yl)-ethyl]- carbamicacid tert- butyl ester

M.S. (M⁺ + 1) 490 142 1H-Pyrazole-4- carboxylic acid [1-(2-hydroxy-3-phenyl- propionyl)-piperidin- 4-ylmethyl]-amide

M.S. (M⁺ + 1) 357 143 1H-Pyrazole-4- carboxylic acid [1-(2-methyl-3-phenyl- propionyl)-piperidin- 4-ylmethyl]-amide

M.S. (M⁺ + 1) 355 144 1H-Pyrazole-4- carboxylic acid {1-[2-hydroxy-3-(4-hydroxy- phenyl)-propionyl]- piperidin-4-ylmethyl}- amide

M.S. (M⁺ + 1) 373 145 1H-Pyrazole-4- carboxylic acid [1-(2-phenyl-cyclopropane- carbonyl)-piperidin-4- ylmethyl]-amide

M.S. (M⁺ + 1) 353

[0174] The following two compounds were prepared from EXAMPLES 140 and141 respectively by treatment with trifluoroacetic acid indichloromethane. EX. Name Structure Analytical Data 146 1H-Pyrazole-4-carboxylic acid [1-(2- amino-3-phenyl- propionyl)-piperidin-4-ylmethyl]-amide

M.S. (M⁺ + 1) 356 147 1H-Pyrazole-4- carboxylic acid {1-[2-amino-3-(4-chloro- phenyl)-propionyl]- piperidin-4-yl- methyl}-amide

M.S. (M⁺ + 1) 390

Example 148 Trans 1H-Pyrazole-4-carboxylic acid[1-(2-phenyl-cyclopropylmethyl)-piperidin-4-ylmethyl]-amide

[0175]

[0176] A solution of 1H-pyrazole-4-carboxylic acid(piperidin-4-ylmethyl)-amide (290 mg, 1.39 mmol),trans-2-phenylcyclopropanecarbaldehyde (224 mg, 1.53 mmol) and sodiumtriacetoxyborohydride (590 mg, 2.78 mmol) in MeOH (15 mL) was heated to50° C. and stirred for 1 h. The resulting reaction mixture wasconcentrated and purified by silica gel chromatography (gradient: CH₂Cl₂to 80:20:2 CH₂Cl₂:MeOH:NH₄OH) to give the trans 1H-pyrazole-4-carboxylicacid [1-(2-phenyl-cyclopropylmethyl)-piperidin-4-ylmethyl]-amideproduct.

[0177]¹H NMR (δ, CDCl₃): 7.86 (s, 2H), 7.23 (d, 2H), 7.17 (t, 1H), 7.02(d, 2H), 5.94 (brt, 1H), 3.35 (m, 2H), 3.10 (brt, 2H), 2.55 (dd, 1H),2.39 (dd, 1H), 2.30 (q, 2H), 1.70-1.55 (m, 4H), 1.41 (m, 2H), 1.22 (m,1H), 0.95 (m, 1H), 0.82 (m, 1H).

[0178] The following compounds were prepared similarly to the proceduredescribed above for EXAMPLE 148 but substituting the appropriatealdehyde for the trans-2-phenylcyclopropanecarbaldehyde. EX. NameStructure Analytical Data 149 1H-Pyrazole-4- carboxylic acid [1-(3-phenyl-propyl)- piperidin-4-ylmethyl]- amide

¹H NMR(δ, CDCl₃): 7.93(s, 2H), 7.3-7.15(m, 5H), 6.30 (brt, 1H), 3.35(t,2H), 3.04(brd, 2H), 2.61(t, 2H), 2.46 (dd, 2H), 2.04(t, 2H), 1.88(m,2H), 1.70(m, 2H), 1.47 (m, 2H), 1.27(t, 1H). 150 1H-Pyrazole-4-carboxylic acid [1- (4-phenyl-butyl)- piperidin-4-ylmethyl]- amide

¹H NMR(δ, CD₃- OD): 8.03(s, 2H), 7.3-7.1(m, 5H), 3.21(d, 2H), 2.97 (brd,2H), 2.63(t, 2H), 2.40(dd, 2H), 2.01(t, 2H), 1.76 (brd, 2H), 1.7-1.5 (m,5H), 1.30(m, 2H). 151 1H-Pyrazole-4- carboxylic acid (1-phenethyl-piperidin- 4-ylmethyl)-amide

M.S. (M⁺ + 1) 313 152 1H-Pyrazole-4- carboxylic acid [1-(2-phenyl-cyclopropyl- methyl)-piperidin-4- ylmethyl]-amide

M.S. (M⁺ + 1) 339 153 1H-Pyrazole-4- carboxylic acid [1-(2-phenyl-cyclopropyl- methyl)-piperidin-4- ylmethyl]-amide

¹H NMR(δ, CDCl₃): 7.86(s, 2H), 7.23(d, 2H), 7.17(t, 1H), 7.00(d, 2H),6.61 (brs, 1H), 3.30(m, 2H), 3.10(brt, 2H), 2.55(dd, 1H), 2.39 (dd, 1H),2.03(q, 2H), 1.70-1.55(m, 4H), 1.41(m, 2H), 1.22(m, 1H), 0.95 (m, 1H),0.82(m, 1H).

[0179] The following compounds were prepared as described above forEXAMPLE 148, but replacing 1H-pyrazole-4-carboxylic acid(pipenidin-4-ylmethyl)-amide with, for example,4-hydroxy-N-piperidin-4-ylmethyl-benzamide, which was prepared from4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester as described in EXAMPLE 137, step 1. EX. Name Structure AnalyticalData 154 4-Hydroxy-N-[1-(2- phenyl-cyclopropyl- methyl)-piperidin-4-ylmethyl]-benzamide

¹H NMR(δ, CDCl₃): 7.43(d, 2H), 7.3-7.1 (m, 3H), 7.00(d, 2H), 6.65(d,2H), 6.39(brt, 1H), 3.35 (m, 2H), 3.14(brt, 2H), 2.58(dd, 1H), 2.41(dd,1H), 2.08 (q, 2H), 1.7-1.5(m, 4H), 1.41(m, 2H), 1.22(m, 1H), 0.96 (m,1H), 0.82(m, 1H). 155 4-Hydroxy-N-[1-(3- phenyl-propyl)-piperidin-4-ylmethyl]- benzamide

¹H NMR(δ, CD₃- OD): 7.70(d, 2H), 7.3-7.1(m, 5H), 6.80(d, 2H), 3.23 (d,2H), 3.02(brd, 2H), 2.61(dd, 2H), 2.42(dd, 2H), 2.08 (brt, 2H), 1.9-1.6(m, 5H), 1.35(m, 2H).

Example 1564-{[(Pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid4-cyclopropyl-benzyl ester

[0180]

Step 1 4-Cyclopropyl-benzoic acid ethyl ester

[0181]

[0182] Indium trichloride (2.2 g, 10 mmol) and THF (50 mL) were combinedunder nitrogen and cooled to −70° C. Cyclopropylmagnesium bromidesolution (33 mL, 30 mmol, 0.92M) was added dropwise while maintainingthe reaction temperature ≦−-60° C. After the addition was complete thereaction was stirred 0.5 h with cooling then 0.5 h with the cooling bathremoved. The resulting solution was added via cannula to a refluxingsolution of ethyl-4-iodobenzoate (5.5 g, 20 mmol),trans-dichlorobis(triphenylphosphine)palladium(II) (421 mg, 0.60 mmol)and THF (100 mL) under nitrogen. After 24 h, the contents of thereaction flask were cooled and the solvent was removed in vactio. Water(100 mL) and 5% KHSO₄ were added and the mixture was extracted withCH₂Cl₂ (3×100 mL). The combined organic extracts were washed with brine,dried with Na₂SO₄ and filtered. The filtrate was removed in vacuo andthe remaining residue was purified by flash column chromatography(hexane:EtOAc 95:5) to give the 4-cyclopropyl-benzoic acid ethyl esteras an orange oil.

Step 2 (4-Cyclopropyl-phenyl)-methanol

[0183]

[0184] 4-Cyclopropyl-benzoic acid ethyl ester (2.46 g, 13 mmol), and THF(250 mL) were combined under nitrogen and cooled in an IPA/dry ice bathto −70° C. Lithium aluminum hydride solution (20 mL, 20 mmol, 1.0M) wasadded dropwise. After 2 h excess lithium aluminum hydride was quenchedby adding EtOAc dropwise. The reaction was warmed to 25° C. then thesolvent was removed in vacuo. Water (200 mL) and a few drops of HCl(aq,6N) were added. The mixture was extracted with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried with Na₂SO₄ andfiltered. The filtrate was removed in vacuo and the remaining residuewas purified by flash column chromatography (hexane:EtOAc 40:60) to givethe (4-cyclopropyl-phenyl)-methanol as a colorless oil.

Step 3 Carbonic acid 4-cyclopropyl-benzyl ester2,5-dioxo-pyrrolidin-1-yl ester

[0185]

[0186] The title compound was prepared from(4—Cyclopropyl-phenyl)-methanol as described above for similar compounds(Chem. Pharm. Bull., 38(1):110-115(1990)).

Step 4 4-Aminomethyl-piperidine-1-carboxylic acid 4-cyclopropyl-benzylester

[0187]

[0188] The title compound was prepared from carbonic acid4-cyclopropyl-benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester as describedin EXAMPLE 1, Step 1.

Step 5 4-{[(Pyridine-4-carbonyl)amino]-methyl}-piperidine-1-carboxylicacid 4-cyclopropyl-benzyl ester

[0189]

[0190] The title compound was prepared from4-aminomethyl-piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester asdescribed above in EXAMPLE 1, Step 2.

[0191] M.S. (M⁺+1) 394

[0192] The following compounds were prepared from4-aminomethyl-piperidine-1-carboxylic acid 4-cyclopropyl-benzyl ester asdescribed above in EXAMPLE 1, step 2. EX. Name Structure Analytical Data157 4-[(4-Hydroxy-ben- zoylamino)-methyl]- piperidine-1-carboxy- licacid 4-cyclopropyl- benzyl ester

M.S. (M⁺ + 1) 409 158 4-{[(1H-Pyrazole-3- carbonyl)-amino]-methyl}-piperidine- 1-carboxylic acid 4- cyclopropyl-benzyl ester

M.S. (M⁺ + 1) 383 159 4-{[(1H-Pyrazole-4- carbonyl)-amino]-methyl}-piperidine- 1-carboxylic acid 4- cyclopropyl-benzyl ester

¹H NMR(500MHz δ, CDCl₃): 10.70(s, br, 1H), 7.95(s, 2H), 7.25(d, 2H),7.05(d, 2H), 600(m, 1H), 5.06(s, 2H), 4.20(s, br, 2H), 3,30(s, br, 2H),2.75(s, br, 2H), 1.90(m, 1H), 1.85-1.50(m, 3H), 1.20 m, 2H), 0.97(m,2H), 0.68(m, 2H).

[0193] The following compounds were prepared from4-hydroxy-N-piperidin-4-ylmethyl-benzamide (prepared from4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester as described in EXAMPLE 137, step 1) as described in EXAMPLE 1,Step 2. EX. Name Structure Analytical Data 160 4-Hydroxy-N-[1-(2-phenyl-cyclopropane- carbonyl)-piperidin-4- ylmethyl]-benzamide

¹H NMR9δ, CDCl₃): 8.729brs, 1H), 7.61 (d, 2H), 7.249m, 2H), 7.199t, 1H),7.069d, 2H), 6.939d, 2H), 6.729brs, 1H), 4.559brd, 1H), 4.10 (brd, 1H)3.3-3.1 (m, 2H), 3.019q, 1H), 2.589brt, 1H), 2.419brs, 1H), 2.0-1.69m,5H), 1.3-1.1 (m, 3H). 161 4-Hydroxy-N-[1-(2- phenyl-cyclopropane-carbonyl)-piperidin-4- ylmethyl]-benzamide

M.S. (M⁺ + 1) 379

Example 162 1H-Pyrazole-4-carboxylic acid(1-benzylthiocarbamoyl-piperidin-4-ylmethyl)-amide

[0194]

[0195] 1H-Pyrazole-4-carboxylic acid (piperidin-4-ylmethyl)-amide(EXAMPLE 137, Step 1) (50 mg, 0.24 mmol), benzyl isothiocyanate (35 μL,0.264 mmol) and DMF (1 mL) were combined and stirred under Nitrogen for1 h. The contents of the reaction flask were poured into water andsodium hydroxide (2 nL, 2N) was added. The resulting mixture wasextracted with EtOAc (3×50 mL) and the combined organic extracts weredried with Na₂SO₄. The filtrate was removed in vacuo and the remainingresidue was purified by Gilson® reverse phase preparative HPLC. Thefraction containing the desired product was evaporated in vacuo to givea colorless oil. Trituration with EtOAc/EtOH afforded the EXAMPLE 162 asa white solid.

[0196]¹H NMR (500 MHz, δ, DMSO-d₆): 13.10 (s, 1H), 8.20 (m, 2H), 8.10(m, 1H), 7.90 (m, 1H), 7.32-7.18 (m, 5H), 4.80 (d, 2H), 4.65 (d, 2H),3.10 (t, 2H), 2.97 (t, 2H), 1.80 (m, 1H), 1.67 (m, 2H), 1.10 (m, 2H).

Example 1634-{[(1H-Pyrazole-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acidbenzylamide

[0197]

[0198] The title compound was prepared as described in EXAMPLE 162except that benzyl isocyanate was used instead of benzyl isothiocyanate.

[0199]¹H NMR (500 MHz, δ, DMSO-d₆): 13.10 (s, 1H), 8.16 (s, 1H), 8.04(m, 1H), 7.88 (s, 1H), 7.30-7.16 (m, 4H), 7.02 (m, 1H), 4.21 (d, 2H),3.99 (d, 2H), 3.10 (t, 2H), 2.65 (m, 2H), 1.72-1.58 (m, 3H), 1.05-0.95(m, 2H).

Example 164 1H-Pyrazole-4-carboxylic acid[1-(2-hydroxy-3-phenyl-propyl)-piperidin-4-ylmethyl]-amide

[0200]

[0201] To a solution of 2-benzyloxirane (0.01 mL, 0.07 mmol) iniso-propyl alcohol (5mL) was added 1H-pyrazole-4-carboxylic acid(piperidin-4-ylmethyl)-amide (EXAMPLE 137, Step 1) (15 mg, 0.07 mmol).The resulting reaction mixture was heated to 60° C. for 24 h. Thereaction mixture was concentrated, partitioned between EtOAc and aqueoussodium bicarbonate. The organic phase was dried, the solvent evaporated,and the crude product purified by reverse phase HPLC to give1H-Pyrazole-4-carboxylic acid[1-(2-hydroxy-3-phenyl-propyl)-piperidin-4-ylmethyl]-amide.

[0202] M.S. (M⁺+1) 343

Example 165

[0203]4-{[(2-Oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

[0204] To4-{[(-oxy-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 115) (200 mg, 0.542 mmol) was added aceticanhydride (5 mL) and the mixture heated to reflux for 24 h. The reactionwas concentrated and chromatographed on silica using ethyl acetate togive an oil (40 mg). The crude material was dissolved in methanol (10mL) and treated with solid potassium carbonate (40 mg) for 0.5 h.Concentration of the reaction and extraction into dichloromethane (20mL) from aqueous sodium bicarbonate (20 mL) followed by concentrationand precipitation of the solid from ether gave the4-{[(2-Oxo-1,2-dihydro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester.

[0205] M.S.(M+1): 370

Example 166

[0206]4-{[(2-Methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

Step 1 Preparation of 2,4-pyridinedicarboxcyclic acid diethyl ester

[0207]

[0208] To a mixture of 2,4-pyridinedicarboxylic acid (23 g, 0.138 mol)in ethanol (500 mL) was bubbled anhydrous hydrogen chloride gas over aperiod of 6 h. The resulting reaction mixture was concentrated in vacuoand extracted into dichloromethane (500 mL) from 10% aqueous sodiumbicarbonate (500 mL). The organic extract was dried over sodium sulfate,and concentrated in vacuo to give 2,4-pyridinedicarboxcyclic aciddiethyl ester as an oil.

[0209] M.S.(M+1): 224

Step 2 Preparation of 2-Formyl-isonicotinic acid ethyl ester

[0210]

[0211] To a solution of 2,4-pyridinedicarboxcyclic acid diethyl ester(25 g, 0.112 mol) in tetrahydrofuran (IL) at −78° C. and under nitrogenwas slowly added a solution of 1.0 M diisobutylaluminum hydride in TF(11 mL). The reaction was stirred at −78° C. for 5 h and then quenchedby addition of a solution of tetrahydrofuran-acetic acid-water (174 mL,62 mL, 15 mL) and the reaction allowed to warm to room temperature.Diethyl ether (500 mL) and 10% aqueous sodium bicarbonate (1L) wereadded and the mixture stirred for 0.5 h. The ether layer was removed andthe aqueous layer extracted with ethyl acetate (4×500 mL) The combinedorganic extracts were washed with saturated sodium chloride andconcentrated to an oil which was purified by silica gel columnchromatography using 30%ethyl acetate/hexane as eluent to give2-formyl-isonicotinic acid ethyl ester as an oil.

[0212] M.S.(M+1): 180

Step 3 Preparation of 2-Diethoxymethyl-isonicotinic acid ethyl ester

[0213]

[0214] To a solution of 2-formyl-isonicotinic acid ethyl ester (5.0 g,0.027 mol) in ethanol (9 mL) was added triethyl orthoformate (6.2 mL,0.037 mol) followed by a solution of 6N hydrochloric acid in ethanol(1.5 mL). The mixture was heated to 110° C. (reflux) for 1.5 h, cooledto rt and solid potassium carbonate (1.80 g) added. The mixture wasstirred for 5 min, concentrated in vacuo, and redissolved in diethylether (100 mL). The reaction was filtered through silica and theresulting cake washed with diethyl ether (50 mL). The filtrated wasconcentrated in vacuo to give 2-diethoxymethyl-isonicotinic acid ethylester as an oil.

[0215] M.S.(M+1): 254

Step 4 Preparation of 2-Diethoxymethyl-isonicotinic acid

[0216]

[0217] To a solution of 2-diethoxymethyl-isonicotinic acid ethyl ester(3.0 g, 0.012 mol) in tetrahydrofuran (100 mL) was added IN sodiumhydroxide (24 mL, 0.024 mol) and mixture allowed to stir for 2 h at rt.The reaction was concentrated in vacuo to give a pasty solid of2-diethoxymethyl-isonicotinic acid, which was used in the next step asis.

[0218] M.S.(M+1): 226

Step 5 Preparation of4-{[(2-Diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

[0219]

[0220]4-{[(2-Diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester was prepared in a similar manner as described inEXAMPLE 1, Step 2.

[0221] M.S.(M+1): 456

Step 6 Preparation of4-{[(2-Formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

[0222]

[0223] To a solution of4-{[(2-diethoxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (1.3 g, 0.0029 mol) in dioxane (20 mL) was added 1Nhydrochloric acid (40 mL) and the mixture was warmed to 50° C. for 1.5h. The reaction was cooled, diluted with ethyl acetate (100 mL) and 10%aqueous sodium bicarbonate (100 mL), and stirred well. The organic layerwas removed, dried over sodium sulfate, filtered and concentrated invacuo to give4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as an oil.

[0224] M.S.(M+1): 382

Step 7 Prep of4-{[(2-Methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

[0225]

[0226] To a solution of4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (50 mg, 0.13 mmol) in dichloroethane (0.5 mL) wasadded acetic acid (8 μL, 0.13 mmol), 2.0 M methylamine in TEF (72 μL,0.14 mmol) followed by sodium triacetoxyborohydride (42 mg, 0.20 mmol).The resulting mixture was stirred for 5 h. The reaction was concentratedin vactio and the residue chromatographed (reverse phase C-18 usingacetonitrile/0.1% trifluoroacetic acid in water) to give uponconcentration in vacuo4-{[(2-methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as the trifluoroacetic acid salt.

[0227] M.S. (m+1) 397

[0228] The following compounds were prepared as described above for4-{[(2-methylaminomethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester, replacing methylamine with the appropriate amine instep 7, EXAMPLE 166. EX. Name Structure Analytical Data 1674-{[(2-Dimethyl- aminomethyl-pyridine- 4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 411 168 4-{[(2-Aminomethyl- pyridine-4-carbonyl)-amino]-methyl}- piperidine-1- carboxylic acid benzyl ester

M.S. (M⁺ + 1) 383

Example 1694-{[(2-Hydroxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

[0229]

[0230] To a solution of4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 166, Step 6) (50 mg, 0.131 mmol) in ethanol(2 mL) was added sodium borohydride (5 mg) and the mixture stirred for0.5 h. The reaction was diluted with 10% aqueous sodium bicarbonate (10mL) and extracted with ethyl acetate (25 mL). The ethyl acetate extractwas concentrated and chromatographed (reverse phase C-18 usingacetonitrile/0.1% trifluoroacetic acid in water) to give uponconcentration in vacuo the4-{[(2-hydroxymethyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as the trifluoroacetic acid salt.

[0231] M.S.(M+1): 384

Example 1704-({[2-(1-Hydroxy-ethyl)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester

[0232]

[0233] To a solution of4-{[(2-formyl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 166, Step 6) (50 mg, 0.131 mmol) in TBF (2mL) at −78° C. was added 3.0M methylmagnesium chloride (45 μL, 0.135mmol). The mixture was stirred for 5 min and allowed to warm to rt. Thereaction was diluted with 10% aqueous sodium bicarbonate (10 mL) andextracted with ethyl acetate (25 mL). The ethyl acetate extract wasconcentrated and chromatographed on silica using 100% ethyl acetate toethyl acetate/methanol (95/5) to give the4-({[2-(1-hydroxy-ethyl)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester.

[0234] M.S. (M⁺+1) 398

Example 1714-({[2-(2,4-Dimethoxy-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester

[0235]

[0236] A mixture of4-{[(2-chloro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 65) (310 mg, 0.8 mmol) and2,4-dimethoxybenzylamnine (1 mL) were heated to 140° C. for 18 h, cooledto rt, and partitioned between pH5.2 citrate buffer and EtOAc. Theorganic layer was dried and the solvent evaporated to give the crudeproduct, purified by chromatography on silica (1:1 hexane EtOAc to 5%MeOH EtOAc to give the4-({[2-(2,4-Dimethoxy-benzylamino)-pyridine4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester.

[0237] M.S. (M⁺+1) 519

Example 1724-{[(2-Amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester

[0238]

[0239]4-({[2-(2,4-Dimethoxy-benzylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 171) (124 mg) in dichloromethane (5 mL) wastreated with trifluoroacetic acid (0.5 mL). After 30 min, the reactionmixture was partitioned between EtOAc and dilute sodium bicarbonatesolution. The organic layer was washed with brine, dried and the solventevaporated to give the crude product which was stirred with ether (3mL)and filtered to give the4-{[(2-amino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester as a white solid.

[0240] M.S. (M⁺+1) 369

Example 1734-({[2-(2-Dimethylamino-ethylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester

[0241]

[0242] A mixture of4-{[(2-chloro-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylicacid benzyl ester (EXAMPLE 65) (50 mg, 0.8 mmol) andN,N-dimethylethylenediamine (0.2 mL) were heated to 100 C. for 18 hours,cooled to room temperature. The reaction mixture was then purified byreverse phase BPLC to give the4-({[2-(2-dimethylamino-ethylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid benzyl ester as its trifluoroacetate salt.

[0243] M.S. (M⁺+1) 440

Example 174N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide

[0244]

Step 1 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester

[0245]

[0246] To a mixture of 15 g of 4-aminomethylpiperidine in 250 mL ofanhydrous tetrahydrofuran cooled to −78° C. was added dropwise over 45min a solution of 24 g of di-tert-butyl di-carbonate in 100 mL ofanhydrous tetrahydrofuran. After stirring for 1 h at −78° C., themixture was allowed to warm to rt and stirred overnight. The mixture wasconcentrated to near dryness and diluted with 200 mL of 10% aqueouscitric acid. The mixture was extracted with 3×100 mL of ether, then madebasic with sodium hydroxide pellets and extracted with 3×200 mL ofchloroform. The combined chloroform extracts were dried over magnesiumsulfate and concentrated to dryness under reduced pressure. Theresulting oil was homogeneous by TLC (development with 90:10 chloroformsaturated with ammonia: methanol).

[0247]¹H NMR (400 MHz, CDCl₃): 4.1 (br s, 2 H), 2.7 (br m, 2H), 2.6 (d,2H), 1.7 (m, 3H), 1.42 (s, 9H), 1.1 (m, 2H).

Step 2 4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester

[0248]

[0249] To a solution of 21 g of 4-aminomethyl-piperidine-1-carboxylicacid tert-butyl ester in 100 mL of ethyl acetate cooled to 0° C. wasadded 100 mL of saturated sodium carbonate and 17 g of benzylchloroformate. The solution was stirred for 3 h, then separated. Theorganic layer was dried over magnesium sulfate and concentrated underreduced pressure. Drying under vacuum gave the product as an oil:

[0250]¹H NMR (400 MHz, CDCl₃): 7.35 (m, 5H), 5.3 (d, 1H), 5.1 (s, 2H),4.1 (br s, 2H), 3.0 (br m, 2H), 2.6 (br m, 2H), 1.7 (m, 3H), 1.42 (s,9H), 1.1 (m, 2H).

Step 3 Piperidin-4-ylmethyl-carbamic acid benzyl ester

[0251]

[0252] A mixture of 35 g of4-(benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester and 50 mL of 4N HCl in dioxane was stirred at rt for 3h, then diluted with 200 mL of ether and filtered. Thepiperidin-4-ylmethyl-carbamic acid benzyl ester hydrochloride salt wasobtained as a white fluffy solid. The free base was obtained bypartitioning the hydrochloride between 50 mL chloroform and 50 mLsaturated aqueous Na₂CO₃.

[0253] MS (m+1)=249; ¹H NMR (400 MHz, CDCl₃)): 7.35 (m, 5H), 5.15 (s,2H), 4.9 (br s, 1 H), 3.1 (m, 2H), 2.6 (m, 3H), 1.7 (m, 2H), 1.6 (m,2H), 1.1 (m, 2H).

Step 4 [1-(2-Phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acidbenzyl ester

[0254]

[0255] A mixture of 2 g of piperidin-4-ylmethyl-carbamic acid benzylester hydrochloride, 25 mL of dichloromethane, 1.5 grams oftrans-2-styrenesulfonyl chloride, and 3 mL of N,N-diisopropylethylaminewas stirred at rt overnight, then diluted with 200 mL of chloroform, andwashed with 100 mL of saturated sodium carbonate. The chloroformextracts were dried over magnesium sulfate and concentrated. The[1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzylester was obtained as a white solid.

[0256] MS (m+1)=415; ¹H NMR (400 MHz, CDCl₃) ): 7.5-7.2 (m, 10H), 6.65(m, 1H), 5.15 (s, 2H), 4.8 (br s, 1H), 3.8 (d, 2H), 3.1 (dd, 2H), 2.6(dd, 2H), 1.8 (d, 2H), 1.6 (m, 2H), 1.35 (m, 2H).

Step 5 C-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine

[0257]

[0258] A mixture of 2.5 g of[1-(2-phenyl-ethenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid benzylester, 1 g of 20% palladium hydroxide on carbon, 200 mL of methanol and50 mL of tetrahydrofuran were shaken under 50 psi of hydrogen for 2 daysat rt. The catalyst was filtered off and washed with 250 mL of methanol.Concentration under reduced pressure gave theC-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine as a whitesolid.

[0259] MS (m+1)=283; ¹H NMR (400 MHz, CDCl₃) ): 7.4-7.2 (m, 5H), 5.1 (s,2H), 3.8 (d, 2H), 3.1 (m, 4H), 2.7 (dd, 2H), 1.8 (d, 2H), 1.6 (m, 5H),1.3 (m, 2H).

Step 6N-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide

[0260]

[0261] TheN-[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-isonicotinamide wasprepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamineand isonicotinic acid as described above in EXAMPLE 1, Step 2.

[0262] MS (m+1)=388.

Example 175N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide

[0263]

Step 1 1-(2—Chloro-ethyl)-4-fluoro-benzene

[0264]

[0265] A mixture of 7 g of 2-(4-fluoro-phenyl)-ethanol, 25 mL ofchlorobenzene, 42 mL of 37% HCl, and 0.9 g of Aliquat® 336(tricaprylylmethyl ammonium chloride) was heated to reflux for 3 days,cooled and extracted into 3×100 mL of hexane. The combined extracts weredried over magnesium sulfate and concentrated under reduced pressure.The resulting oil was a crude product of1-(2-chloro-ethyl)-4-fluoro-benzene:

[0266]¹H NMR (400M, CDCl₃): 7.3 (dd, 2H), 7.0 (dd, 2H), 3.7 (t, 2H),3.05 (t, 2H).

Step 2 Thioacetic acid S-[2-(4-fluoro-phenyl)-ethyl] ester

[0267]

[0268] A mixture of 2.4 g of 1-(2-chloro-ethyl)-4-fluoro-benzene, 30 mLof DMF, and 2.5 g of potassium thioacetate was stirred under nitrogenfor 24 h. The mixture was diluted with 200 mL of water and extractedwith 3×50 mL of dichloromethane. The combined organic layers were driedover magnesium sulfate and concentrated under reduced pressure. Dryingunder vacuum gave the product as an oil:

[0269]¹H NMR (400 MHz, CDCl₃): 7.18 (dd, 2H), 6.98 (dd, 2H), 3.08 (t,2H), 2.81 (t, 2H), 2.32 (s, 3H).

Step 3 2-(4-Fluoro-phenyl)-ethanesulfonyl chloride

[0270]

[0271] A stream of chlorine gas was dispersed into a stirred, ice coldmixture of 2.5 g of thioacetic acid S-[2-(4-fluoro-phenyl)-ethyl] ester,30 mL of dichloromethane and 30 mL of water over 1 h. The mixture wasdiluted with 200 mL of dichloromethane, shaken and separated. Thecombined organic layers were dried over magnesium sulfate andconcentrated under reduced pressure. Trituration with hexane gave awhite solid:

[0272]¹H NMR (400 MHz, CDCl₃): 7.2 (dd, 2H), 7.0 (dd, 2H), 3.1 (dd, 2H),3.3 (dd, 2H), 2.32 (s, 3H).

Step 4 4-(tert-Butoxycarbonylamino-methyl)-piperidine-1-carboxylic acidbenzyl ester

[0273]

[0274] To an ice cold, stirred solution of 21 g of4-aminomethyl-piperidine-1-carboxylic acid benzyl ester in 250 mL ofdichloromethane was added 18 g of di-tert-butyldicarbonate in 100 mL ofdichloromethane over 30 min. After stirring overnight, the mixture wasconcentrated to dryness. Trituration with hexane gave a white solid:

[0275] 1H NMR (400 MHz, CDCl₃): 7.4 (m, 5H), 5.15 (s, 2H), 4.6 (br s,1H), 4.2 (br s, 2H), 3.0 (br s, 2H), 2.8 ((m, 2H), 1.7 (m, 3H), 1.42 (s,9H), 1.15 (m,2H).

Step 5 Piperidin-4-ylmethyl-carbamic acid tert-butyl ester

[0276]

[0277] A mixture of 28 g of4-(tert-butoxycarbonylamino-methyl)-piperidine-1-carboxylic acid benzylester, 1 g of 10% palladium on carbon, 100 mL of THF and 200 mL ofmethanol was stirred under an atmosphere of hydrogen for 2 days. Themixture was filtered concentrated under reduced pressure. Drying underreduced pressure gave a white solid:

[0278]¹H NMR (400 MHz, CDCl₃): 4.8 (br s, 1H), 3.05 (d, 2H), 2.9 (dd,2H), 2.6 (m, 3H), 1.6 (d, 2H), 1.5 (m, 1H), 1.4 (s, 9H), 1.05 (m, 2H).

Step 6{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-carbamicacid tert-butyl ester

[0279]

[0280] To an ice cold, stirred solution of 0.2 g ofpiperidin-4-ylmethyl-carbamic acid tert-butyl ester and 0.2 mL ofN,N-diisopropylethyl amine in 20 mL of dichloromethane was added 0.3 gof 2-(4-fluoro-phenyl)-ethanesulfonyl chloride. After stirringovernight, the mixture was diluted with 50 mL of chloroform, washed with50 mL of saturated sodium carbonate, dried over magnesium sulfate andconcentrated to dryness under reduced pressure. Trituration with hexanegave a white solid:

[0281]¹H NMR (400 MHz, CDCl₃): 7.2 (m, 2H), 7.0 (dd, 2H), 4.6 (br m,1H), 3.8 (d, 2H), 3.1 (m, 3H), 3.0 (m, 2H), 2.7 (dd, 2H), 1.8 (d, 2H),1.6 (br m, 2H), 1.42 (s, 9H), 1.3 (m, 2H).

Step 7C-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine

[0282]

[0283] A mixture of 0.4 g of{1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-carbamicacid tert-butyl ester and 5 mL of 4N HCl in dioxane was stirred at rtfor 3 h, then diluted with 50 mL of chloroform, washed with 50 mL ofsaturated sodium carbonate, dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The product was a whitesolid:

[0284] MS (m+1)=301; ¹H NMR (400 MHz, CDCl₃): 7.2 (m, 2H), 7.0 (dd, 2H),3.92 (d, 2H), 3.1 (s, 4H), 2.7 (dd, 2H), 2.6 (d, 2H), 1.8 (d, 2H), 1.5(br m, 3H), 1.3 (m, 2H).

Step 8N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide

[0285]

[0286]N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamidewas prepared fromC-{1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamineand 4-hydroxybenzoic acid as described above in EXAMPLE 1, Step 2

[0287] MS (m+1)=421.

[0288] The following compounds were prepared as described in EXAMPLE175, but replacing the 4-fluorophenethyl alcohol with the appropriatelysubstituted phenethyl alcohol in Step 1 and using the appropriatecarboxylic acid in Step 8. EX. Name Structure Analytical Data 176N-[1-(2-p-Tolyl- ethanesulfonyl)- piperidin-4- ylmethyl]-isonicotinamide

MS (m + 1) = 402.5. 177 3H-Benzoimidazole- 5-carboxylic acid [1-(2-phenyl-ethane- sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 427.5. 178 Pyrimidine-4- carboxylic acid [1-(2-phenyl-ethane- sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 389. 179 2-Amino-pyrimidine- 5-carboxylic acid[1-(2-phenyl-ethane- sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 391 180 Pyrazine-2- carboxylic acid [1-(2- phenyl-ethane-sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 389 181 3-Amino-pyrazine-2- carboxylic acid [1-(2-phenyl-ethane- sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 404 182 Pyrimidine-5- carboxylic acid [1-(2- phenyl-ethane-sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 389 183 Pyrimidine-4- carboxylic acid [1-(2-p-tolyl-ethane- sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 389 184 9H-Purine-6- carboxylic acid [1-(2- phenyl-ethane-sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 429 185 N-{1-[2-(4-Chloro- phenyl)-ethane-sulfonyl]-piperidin-4- ylmethyl}-4-hydroxy- benzamide

MS (m + 1) = 437 186 N-{1-[2-(2-Fluoro- phenyl)-ethane-sulfonyl]-piperidin-4- ylmethyl}-4-hydroxy- benzamide

MS (m + 1) = 421 187 6-Hydroxy-N-[1-(2- phenyl-ethane-sulfonyl)-piperidin-4- ylmethyl]- nicotinamide

MS (m + 1) = 404 188 4-Hydroxy-N-[1-(2- phenyl-ethane-sulfonyl)-piperidin-4- ylmethyl]-benzamide

MS (m + 1) = 403 189 Pyridazine-4- carboxylic acid [1-(2- phenyl-ethane-sulfonyl)-piperidin-4- ylmethyl]-amide

MS (m + 1) = 389

Example 190 (R,S)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester

[0289]

Step 1 1-Benzyl-pyrrolidine-3-carboxylic acid amide

[0290]

[0291] To a mixture of 4.4 g of 1-benzyl-pyrrolidine-3-carboxylic acidmethyl ester (M. J. Kornet et al., J. Org. Chem., 33:3637-3639(1968))and 3 g of formamide in 10 mL of anhydrous DMF heated to 100° C. wasadded a solution of sodium methoxide, from 0.33 g of sodium dissolved inmethanol, dropwise over 20 min. After stirring for 1 h at 100° C., themixture was allowed to cool to rt and added to 100 mL of isopropanol.The mixture was concentrated to dryness. The resulting residue wastriturated with 200 mL of chloroform, filtered and concentrated todryness under reduced pressure. The resulting oil was fairly homogeneousby TLC (development with 90:10 chloroform saturated with ammonia:methanol):

[0292]¹H NMR (400 MHz, CDCl₃): 7.1 (5H), 4.3 (br s, 2 H), 3.5 (d, 2H),3.4 (m, 1H), 2.6 (m, 2H), 2.5 (m, 1H), 2.25 (m, 1H), 1.9 (m, 1H).

Step 2 3-Carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester

[0293]

[0294] A mixture of 4.5 g of 1-benzyl-pyrrolidine-3-carboxylic acidamide, 200 mL of THF, 20 mL of methanol, and 1 g of 20% palladiumhydroxide on carbon was shaken under 50 psi of hydrogen for 12 h. Thecatalyst was filtered off and the filtrate concentrated under reducedpressure. Drying under vacuum gave 3 g of an oil. To a stirred solutionof the crude residue in 500 mL of chloroform was added 5.5 g ofN-(benzyloxycarbonyloxy)succinimide and 2.2 mL of triethylamine. Themixture was allowed to stir overnight and washed with 50 mL of saturatedsodium carbonate dried over magnesium sulfate and concentrated todryness. Purification by chromatography on silica gel, eluting with90:10 ethyl acetate: methanol, gave the product as a resin:

[0295]¹H NMR (400 MHz, CDCl₃): 7.35 (m, 5H), 5.6 (br m, 2H), 3.6 (m,3H), 3.4 (m, 1H), 2.9 (br m, 1H), 2.1 (m, 2H).

Step 3 3-Aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester

[0296]

[0297] A mixture of 1 g of 3-carbamoyl-pyrrolidine-1-carboxylic acidbenzyl ester and 24 mL of 1M borane-THF was stirred at room temperaturefor 24 h, then quenched with 50 mL of 3N HCl. The mixture wasconcentrated under reduced pressure, followed by being partitionedbetween 50 mL chloroform and 25 mL saturated aqueous sodium carbonate.Concentration of the combined extracts after drying over magnesiumsulfate gave the product as a resin:

[0298]¹H NMR (400 MHz, CDCl₃)): 7.35 (m, 5H), 5.15 (s, 2H), 3.7-4(complex, 4H), 2.7 (m, 1H), 2.4-2.0 (complex, 2H), 1.6 (m, 4H).

Step 4 (R,S)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester

[0299]

[0300] (R,S)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester was prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acidbenzyl ester and 4-hydroxybenzoic acid as described above in EXAMPLE 1,Step 2.

[0301] MS (m+1)=395.

Example 191 (R)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester and (S)3-[(4-Hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester

[0302]

[0303] Resolution of (R,S)3-[(4-hydroxy-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid benzylester (EXAMPLE 190) was performed on a Chirapak® preparative chiral KPLCcolumn:

[0304] MS (m+1)=395.

Example 192 2-Amino-pyrimidine-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide

[0305]

Step 1(5-{[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]carbamoyl}-pyrimidin-2-yl)-carbamicacid tert-butyl ester

[0306]

[0307](5-{[1-(2-Phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamicacid tert-butyl ester was prepared fromC-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and2-tert-butoxycarbonylaminopyrimidine-5-carboxylic acid (prepared by BOCprotection of ethyl 2-amino-5-pyrimidine carboxylate [prepared asdescribed by P. Schenone, et al., J. Heterocyclic Chem.,27:295-305(1990)] using di-tert-butyl dicarbonate and4-dimethylaminopyridine in acetonitrile, followed by saponification withsodium hydroxide and neutralization with dilute aqueous HCl) asdescribed in EXAMPLE 1, Step 2:

[0308] MS (m+1)=504.

Step 2 2-Amino-pyrimidine-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide

[0309]

[0310] 2-Amino-pyrimidine-5-carboxylic acid[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide was preparedfrom(5-{[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-carbamoyl}-pyrimidin-2-yl)-carbamicacid tert-butyl ester by stirring at rt for 3 h in 4N HCl in dioxane.The product was precipitated as the hydrochloride salt by dilution withether and filtration.

[0311] MS (m+1)=404.

Example 193 2-Amino-pyrimidine-5-carboxylic acid[1-(2-p-tolyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide

[0312]

[0313] The title compound was prepared fromC-[1-(2-p-tolyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and2-tert-butoxycarbonylamino-pyrimidine-5-carboxylic acid, followed bytreatment with 4N HCl in dioxane as described in EXAMPLE 192.

[0314] MS (m+1)=418.

[0315] The following compounds were prepared by coupling4-aminomethyl-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 1,Step 1) with the appropriate acid as described in EXAMPLE 1, Step 2. EX.Name Structure Analytical Data 194 4-{[(3-Methyl-3H- imidazole-4-carbonyl)-amino]- methyl}-piperidine-1- carboxylic acid benzyl ester

MS (m + 1) = 357 195 4-{[(3-Methyl-3H- imidazole-4- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4- methyl-benzyl ester

MS (m + 1) = 371 196 4-{[(9H-Purine-6- carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester

MS (m + 1) = 395

Example 1973-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

[0316]

Step 1 1-Benzyl-4-hydroxymethyl-piperidin-3-ol

[0317]

[0318] Sodium borohydride (40 g) was added in portions to a stirredsolution of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloridein methanol (500 mL), over 2 h. Water (300 mL) was added slowly, themixture stirred for 15 min, and then the organics were evaporated. Theresulting residue was partitioned between DCM and water (×3), thecombined organic layers dried over anhydrous sodium sulfate, and thesolvent evaporated to give the product as a cis trans mixture, used inthe next step without further purification.

[0319] M.S. (M+1): 222.

Step 2 3-Hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid benzylester

[0320]

[0321] A solution of the 1-Benzyl-4-hydroxymethyl-piperidin-3-ol fromStep 1 above (13.5 g) in methanol (450 mL) was hydrogenated at 50 psiover 20% palladium hydroxide on charcoal (10 g) for 48 h in threebatches. The combined reaction mixtures were filtered and the filtrateevaporated to give an oil. This oil was dissolved in water (100 mL) anddioxane (100 mL), cooled to 5° C., and benzyl chloroformate (7.8 mL) wasadded slowly. 1M NaOH was added to maintain pH of 10-11. After 30 min,the cooling bath was removed and reaction mixture stirred for 30 min.The reaction mixture was concentrated to remove dioxane and the residueextracted with EtOAc (×3). The combined extracts were washed with brine,dried over anhydrous sodium sulfate and solvent evaporated to give amixture of cis and trans products. Purified by flash columnchromatography (80% EtOAc hexane to 5% MeOH EtOAc) gave the upper Rf cisisomer and the lower Rf trans isomer.

[0322] M.S. (M+l): 266.

Step 3 Cis3-Hydroxy-4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acidbenzyl ester

[0323]

[0324] A solution of the3-Hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester diolfrom Step 2 above (7.65 g) in chloroform (200 mL) was treated withpyridine (2.6 mL) and 4-toluenesulfonyl chloride (6.05 g) and thereaction mixture heated to 60° C. for 18 h. Additional pyridine (0.85mL) and 4-toluenesulfonyl chloride (2.0 g) were added to the cooledreaction and heating continued for a further 24 h. The reaction mixturewas cooled to rt and washed with 10% aqueous citric acid solution andwater, dried over anhydrous sodium sulfate and the solvent evaporated togive, after flash column chromatography, the Cis3-Hydroxy-4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acidbenzyl ester.

Step 4 Cis 4-Aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzylester

[0325]

[0326] A solution of the cis3-Hydroxy-4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acidbenzyl ester (6.80 g) from Step 3 above was dissolved in DME (50 mL) andtreated with sodium azide (3.16 g). The reaction mixture was then heatedto 50° C. for 48 h, cooled to rt, and partitioned between dilute aqueoussodium bicarbonate and EtOAc. The organic layer was washed with brine,dried over anhydrous sodium sulfate and solvent evaporated to give theazide, which was dissolved in THF (50 mL) and treated withtriphenylphosphine (14.07 g) and water (3.25 mL). The reaction mixturewas stirred for 18 h at rt, the volatiles evaporated, and the residuepurified by flash column chromatography (DCM to 80/20/2 DCM MeOH NH₄OH)to give the cis 4-Aminomethyl-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester as an oil.

[0327] M.S. (M+1): 265.

Step 43-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

[0328]

[0329] The3-Hydroxy-4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester was prepared from the cis4-Aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (Step3 above) and 4-hydroxybenzoic acid as described in EXAMPLE 1, Step 2.

Example 198 3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylicacid benzyl ester

[0330]

Step 1 4-Hydroxy-N-pyridin-3-ylmethyl-benzamide

[0331]

[0332] The 4-hydroxy-N-pyridin-3-ylmethyl-benzamide was prepared from3-(2-aminomethyl)pyridine and 4-hydroxybenzoic acid in as described inEXAMPLE 1, Step 2.

[0333] M.S. (M+1): 229.

Step 2 4-Hydroxy-N-piperidin-3-ylmethyl-benzamide

[0334]

[0335] To a solution of 4-hydroxy-N-pyridin-3-ylmethyl-benzamide (2.0 g,0.0088 mol) in acetic acid (135 mL) was added platinum oxide (200 mg)and the mixture stirred under hydrogen for 3 h. The reaction wasfiltered and concentrated in vacuo to give an oil.

[0336] M.S. (M+1): 235.

Step 3 3-[(4-Hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acidbenzyl ester

[0337]

[0338] To a mixture of 4-hydroxy-N-piperidin-3-ylmethyl-benzamide (135mg, 0.580 mmol) in tetrahydrofuran (5 mL) was added triethylamine (100μL) and N-benzyloxycarbonyloxysuccinamide (144 mg, 0.580 mmol) and themixture stirred at rt for 3 h. The reaction was concentrated in vacuoand chromatographed on silica using 50-100% ethyl acetate/hexane to give3-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzylester as a foam.

[0339] M.S. (M+1): 369.

Example 199 3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylicacid benzyl ester

[0340]

Step 1 1,4-Dibenzyl-2-chloromethyl-piperazine

[0341]

[0342] The above compound was prepared according to the proceduredescribed in Bihan, G. et. al., J. Med. Chem., 42:1587-1603(1999).

Step 2 2-Azidomethyl-1,4-dibenzyl-piperazine

[0343]

[0344] To a solution of 1,4-dibenzyl-2-chloromethyl-piperazine (8.8 g,0.028 mol) in dimethylformamide (90 mL) under nitrogen was added sodiumazide (5.5 g) and the reaction stirred at 50° C. for 18 h. The reactionwas cooled and diluted with 10% aqueous sodium bicarbonate (100 mL) andwater (250 mL) and the mixture extracted with ethyl acetate (2×200 mL).The organic extracts were washed with 10% sodium bicarbonate, brine,dried over sodium sulfate and concentrated to an oil.

[0345] M.S. (M+1): 322.

Step 3 C-(1,4-Dibenzyl-piperazin-2-yl)-methylamine

[0346]

[0347] To a solution of 2azidomethyl-1,4-dibenzyl-piperazine (9.0 g,0.028 mol) in TBFE (90 mL) and water (5 mL) was added triphenylphosphine(22.3 g, 0.085 mol) and the mixture stirred for 18 h. The reaction wasconcentrated to an oil, dissolved in 1N hydrochloric acid (100 mL) andwashed with ethyl acetate (2×100 mL). The acidic aqueous layer wascooled to 0° C. and the pH adjusted to 8.5 with 3N sodium hydroxide. Themixture was extracted with ethyl acetate (2×100 mL) and extracts driedover sodium sulfate and concentrated to an oil.

[0348] M.S. (M+1): 296.

Step 4 N-(1,4-Dibenzyl-piperazin-2-ylmethyl)-4-hydroxy-benzamide

[0349]

[0350] The N-(1,4-Dibenzyl-piperazin-2-ylmethyl)-4-hydroxy-benzamide wasprepared from C-(1,4-Dibenzyl-piperazin-2-yl)-methylamine and4-hydroxybenzoic acid as described in EXAMPLE 1, Step 2.

[0351] M.S. (M+1): 416.

Step 5 4-Hydroxy-N-piperazin-2-ylmethyl-benzamide

[0352]

[0353] The 4-Hydroxy-N-piperazin-2-ylmethyl-benzamide was preparedaccording to the procedure described in EXAMPLE 198, Step 2, using 10%Palladium/Carbon as catalyst in ethanol/12N HCl at 50° C. for 5 h.

[0354] M.S. (M+1): 236.

Step 6 3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acidbenzyl ester

[0355]

[0356] The 3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylicacid benzyl ester was prepared according to the procedure described inEXAMPLE 198, Step 3. Dilution of reaction with 10% aqueous sodiumbicarbonate and extraction with ethyl acetate followed by concentrationand purification by silica gel chromatography using 95/5/1 to 90/10/2(dichloromethane/methanol/NH4OH) gave the3-[(4-Hydroxy-benzoylamino)-methyl]-piperazine-1-carboxylic acid benzylester as a solid.

[0357] M.S. (M+1): 370.

Example 2004-Hydroxy-N-[4-(3-phenyl-propionyl)-piperazin-2-ylmethyl]-benzamide

[0358]

[0359] The title compound was prepared in a similar manner as describedin EXAMPLE 1, Step 2, from 4-hydroxy-N-piperazin-2-ylmethyl-benzamideand 4-hydroxybenzoic acid.

[0360] M.S. (M+1): 368.

Example 2014-Hydroxy-N-[4-(3-phenyl-propyl)-piperazin-2-ylmethyl]-benzamide

[0361]

[0362] The title compound was prepared in a similar manner as describedin EXAMPLE 148, Step 1, from 4-Hydroxy-N-piperazin-2-ylmethyl-benzamideand propionaldehyde in dichlorethane as solvent.

[0363] M.S. (M+1): 354.

Example 202 2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine-4-carboxylicacid benzyl ester

[0364]

Step 1 N-(4-Benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide

[0365]

[0366] The N-(4-Benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide wasprepared from C-(4-benzyl-morpholin-2-yl)-methylamine (S. Kato et al.,J. Med Chem., 33:1406(1990)) similarly to the procedure described inEXAMPLE 1, Step 2.

[0367] M.S. (M+1): 327

Step 2

[0368]

[0369] A solution ofN-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (Step 1 above)(320 mg) was dissolved in ethanol (20 mL) and hydrogenated at 1 atm over20% Pd(OH)₂/C (250 mg) for 18 h. The catalyst was removed by filtration,washed with ethanol, and the filtrate evaporated, to give a solid. Aportion (21 mg) of this material was dissolved in DMF (0.5 mL) andN-(benzyloxycarbonyloxy)succinimide (27 mg) was added. The reactionmixture was stirred for 10 min, one drop of water was added and thesolution was purified by preparative reverse phase HPLC to give the2-[(4-Hydroxy-benzoylamino)-methyl]-morpholine4-carboxylic acid benzylester compound.

[0370] M.S. (M+1): 371

Example 2034-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamide

[0371]

[0372] A solution ofN-(4-benzyl-morpholin-2-ylmethyl)-4-hydroxy-benzamide (EXAMPLE 202,Step 1) (55 mg) was dissolved in acetic acid (3 mL) and hydrogenated at1 atm over 10% Pd/C (50 mg) for 18 h. The catalyst was removed byfiltration, washed with acetic acid and the filtrate evaporated, to givean oil. A portion of this oil (21 mg) was dissolved in methanol (1 mL)and treated with phenylpropionaldehyde (24 mg) and sodiumcyanoborohydride (25 mg). The resulting reaction was stirred for 15 minand the crude reaction mixture purified by preparative reverse phaseIPLC to give the4-Hydroxy-N-[4-(3-phenyl-propyl)-morpholin-2-ylmethyl]-benzamidecompound.

[0373] M.S. (M+1): 355

Acid Intermediates 4-(1-Hydroxyethyl)benzoic acid

[0374]

[0375] To a solution of methyl 4-(1-hydroxyethylbenzoate (150 mg, 0.83mmol) in TBF (1 mL) was added 1M LiOH (1 mL). The reaction mixture washeated to 60° C. and stirred for 1 h. After cooling, the reaction wasacidified with 1M HCl, and extracted with EtOAc twice. The organic layerwas dried over Na₂SO₄, filtered and concentrated to give4-(1-hydroxyethyl)benzoic acid as a white solid which was used withoutfurther purification.

4-(2-Hydroxyethyl)benzoic acid

[0376]

[0377] To a solution of 0.5 g (3.40 mmol) of the nitrile and 20 mLethanol was added 7 mL of 2N NaOH. The solution was heated at 98° C. for18 h., cooled, then evaporated. The remaining oil was dissolved intoEtOAc and aqueous sodium bicarbonate. The organic layer was discarded.The aqueous layer was acidified with 6N HCl, extracted into EtOAc, driedover Na₂SO₄, filtered and evaporated to yield the hydroxy acid as awhite solid.

4-(1H-Imidazol-2-yl)benzoic acid

[0378]

[0379] Ammonia gas was bubbled into a solution of 4-carboxybenzaldehyde(2.0 g, 13.32 mmol) in water (15 mL) for 10 min. To clear soln was addedglyoxal (2.9 mL, 19.98 mmol) in water (10 mL) dropwise over 15 min andthe reaction mixture was stirred for 3 h. The solution was neutralizedwith 6N HCl and filtered to give a white paste. Trituration with acetonefollowed by evaporation gave 4-(1H-imidazol-2-yl)benzoic acid as a whitesolid.

2-(Hydroxymethyl)-1,3-thiazole-4-carboxylic acid

[0380]

Step 1 Preparation of2-{[(2,2-dimethylpropanoyl)oxy]methyl}-1,3-thiazole-4-carboxylic acid

[0381]

[0382] To a solution of bromopyruvic acid (0.37 g, 2.22 mmol) and2-(tert-butylcarbonyloxy)thioacetamide (0.41 g, 2.22 mmol) in ethanol(20 ml) was added 4 A molecular sieves (2 g). After stirring for 15 h,20 mL of dichloromethane was added. The mixture was stirred 5 min andfiltered to give the product as a yellow solid.

Step 2 Preparation of 2-(hydroxymethyl)-1,3-thiazole-4-carboxylic acid

[0383]

[0384] To the protected alcohol acid (0.36 g, 1.48 mmol) in MeOH (20 mL)and water (6 mL) was added potassium carbonate (0.36 g, 0.26 mmol). Themixture was heated at reflux for 2 h. The methanol was removed in vacuoand the remaining aqueous reaction mixture was extracted with hot EtbAc(2×100 mL). The combined organic layers were dried over Na₂SO₄, filteredand evaporated to a yellow oil. Diethyl ether (20 mL) was added, and themixture was decanted and dried in vacuo to give the product as a brownpowder.

Example 204 4-Methylbenzyl4-({[4-(1-hydroxy-1-methylethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

[0385]

[0386] To a 0° C. solution of 4-methylbenzyl4-({[4-(methoxycarbonyl)benzoyl]-amino}methyl)-piperidine-1-carboxylate(EXAMPLE 538) (100 mg, 0.24 mmol) in THF (3 mL) was added methylmagnesiumbromide (0.39 mL, 1.18 mmol, 3.0M in Et₂O). The reactionmixture was warmed to rt, quenched with H₂O and extracted with EtOAc.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed on silica gel (gradient elution, 2:1hexane:EtOAc to EtOAc) to give 4-methylbenzyl4-({[4-(1-hydroxy-1-methylethyl)benzoyl]amino}methyl)piperidine-1-carboxylate.

[0387] (M+H)⁺=425.5

Example 205 4-Methylbenzyl4-({[3-(hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

[0388]

[0389] To a solution of 4-methylbenzyl4-({[3-(methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate(EXAMPLE 540) (100 mg, 0.24 mmol) in MeOH (2 mL) was added sodiumborohydride (0.18 mg, 4.7 mmol). The solution was stirred at rt for 2 h,quenched with saturated NH₄Cl (aq) and extracted with EtOAc. The organiclayer was dried over NaSO₄, filtered and concentrated. The residue waschromatographed on silica gel (gradient elution, 2:1 hexane:EtOAc toEtOAc) to give 4-methylbenzyl4-(([3-(hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate.

[0390] (M+H)⁺=397.5

Example 206 4-Methylbenzyl4-[({[3-(hydroxymethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

[0391]

[0392] To5-({[(1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)methyl]amino}carbonyl)-1H-pyrazole-3-carboxylicacid (50 mg, 0.13 mmol) was added BH,-THF solution (2.5 mL, 2.5 mmol,1.0M in THE). The solution was stirred at rt for 1 h, quenched with HCl(1M) and extracted with EtOAc. The organic layer was washed with HOdried over Na2SO₄, filtered and concentrated. The residue waschromatographed on silica gel (gradient elution, EtOAc to 10%MeOH/EtOAc) to give 4-methylbenzyl4-[({[3-(hydroxymethyl)-1H-pyrazol-5-yl]carbonyl}amino)methyl]piperidine-1-carboxylate.

[0393] (M+H)⁺=387.5

Example 207 Benzyl4-({[(2-aminopyrinmidin-4-yl)carbonyl]amino}-methyl)piperidine-1-carboxylate

[0394]

Step 1 To P reparation of 1-bromo-2-(methylthio)pyrimidine-4-carboxylicacid

[0395]

[0396] To a stirring solution of mucobromic acid (28.1 g, 109 mmol) and2-methyl-2-thiopseudourea sulfate (21.4 g, 109 mmol) in water (400 mL)under an argon atmosphere was added triethylamine (45.6 mL, 327 mmol)via a syringe pump (˜3 mL/h). After 18 h, conc. HCl (14 mL) was added tothe dark brown solution, stirred 30 min, then filtered. The resultingsolid was washed with water and dried to yield a brown solid. The solidwas dissolved in 400 mL water, and the pH was adjusted to ˜8 with solidsodium bicarbonate slowly to form a solution. To the solution, 10 g ofNorit decolorizing charcoal was added and the suspension was heated for1.25 h. at 100° C., cooled, then filtered through a pad of Celite. ThepH of the solution was adjusted to ˜0.3 with conc. HCl, allowed to stirin an ice bath for 30 min then filtered to yield 16.0 g of yellow solidafter drying in air.

Step 2 Preparation of 2-(methylthio)pyrimidine-4-carboxylic acid

[0397]

[0398] A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid(8.0 g, 32.1 mmol) and potassium hydroxide (4.4 g, 32.1 mmol) in MeOH(175 mL) was transferred to a Parr hydrogenation jar. After purging thesolution with nitrogen gas, of 5% Pd on barium sulfate (3.93 g) wasadded then hydrogenated on Parr Hydrogenation Apparatus for 2 h at 40psi. The mixture was filtered through a Celite pad. The resulting yellowsolution was evaporated to 30 mL, then conc HCl was added to pH 0.3,yielding a yellow solid carboxylic acid after filtration and air drying.

Step 3 Preparation of 2-(methylsulfonyl)pyrimidine-4-carboxylic acid

[0399]

[0400] To a solution of 2-(methylthio)pyrimidine-4-carboxylic acid (1.88g (11.1 mmol) in THf (200 mL) was added Oxone (20.4 g, 33.1 mmol) inwater (50 mL). The suspension was stirred for 24 h, then evaporated todryness. The resulting white paste was extracted 5× each 100 mL EtOAcand 5% MeOH in EtOAc. The combined extracts were dried over anhydrousMgSO₄, filtered and concentrated to give the sulfone as a white solid.

Step 4 Preparation of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

[0401]

[0402] 2-(Methylsulfonyl)pyrimidine-4-carboxylic acid was coupled tobenzyl 4-(aminomethyl)piperidine-1-carboxylate according to theprocedure for EXAMPLE 1.

Step 5 Preparation of benzyl4-({[(2-aminopyrimidin-4-yl)carbonyl]amino}-methyl)piperidine-1-carboxylate

[0403]

[0404] Ammonia gas was bubbled through a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (1.30 g, 3.01 mmol) in EtOAc (75 mL) for 10 min.The resulting solution was heated in a sealed pressure tube for 18 h. at65° C. The white suspension was then concentrated in vacuo. The mixturewas recrystallized using ˜20 mL EtOAc, and a minimal amount of MeOH,providing EXAMPLE 207 as a white solid. (M+H)⁺=370.4

Example 208 Benzyl4-[({[2-(methylamino)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

[0405]

[0406] To a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (0.90 g, 3.01 mmol) in THF (75 mL) was added 40%aqueous methylamine (0.45 g). The resulting solution was heated for 18 hat 65° C., evaporated to dryness and purified by silica gelchromatography (gradient elution, 30 to 100% ethyl acetate in hexane) toprovide EXAMPLE 208 as a yellow gum. (M+H)⁺=384.3

Example 209 Benzyl4-[({[2-(dimethylamino)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate

[0407]

[0408] To a solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (43 mg, 0.01 mmol) in THF (10 mL) was addeddimethylamine hydrochloride (23.6 mg, 0.3 mmol). The resulting solutionwas heated for 18 h at 80° C. and evaporated to dryness. Ethyl acetatewas added, and washed with sat'd aqueous sodium bicarbonate, water thenbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The resulting oil was purified by silica gelchromatography (gradient elution, 20 to 100% ethyl acetate in hexane) toprovide EXAMPLE 209 as a white foam. (M+H)⁺=398.3

Example 210 Benzyl4-({[(2-hydroxypyrimidin-4-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

[0409]

[0410] To a solution of benzyl4-[(([2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (70 mg, 0.20 mmol) in THF (3 mL) was added NH₄OH(0.5 mL). The solution was stirred at rt for 2 h. The solution wasevaporated, water was added then extracted 2× with EtOAc, dried overNa₂SO₄, and evaporated to an oil. Silica gel column chromatography usinga 95:5:0.5 to 90:10:1 CH₂Cl₂:MeOH:NH₄OH gradient provided EXAMPLE 210 asa white solid. (M+H)⁺=371.4

Example 211 Benzyl4-({[(2-methoxypyrimidin-4-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

[0411]

[0412] A solution of benzyl4-[({[2-(methylsulfonyl)pyrimidin-⁴-yl]carbonyl}amino)methyl]piperidine-1-carboxylate(EXAMPLE 207, Step 4) (70 mg, 0.20 mmol) in MeOH (3 mL) was heated at60° C. for 18 h. The solution was evaporated, water was added thenextracted 2×with EtOAc, dried over Na₂SO₄, and evaporated to an oil.Silica gel column chromatography using a 95:5:0.5 to 90:10:1CH₂Cl₂:MeOH:NH₄OH gradient provided EXAMPLE 211 as a white solid.(M+H)⁺=385.4

Example 212 4-Methylbenzyl4-({[4-(2,2,2-trifluoro-1-hydroxyethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

[0413]

[0414] To a solution of 4-methylbenzyl4-({[4-(trifluoroacetyl)benzoyl]amino}methyl)piperidine-1-carboxylate(EXAMPLE 543) (250 mg, 0.54 mmol) in methanol (10 mL) was added sodiumborohydride (20.5 mg, 0.54 mmol). After 1 h., water (10 mL) was addedand the organics evaporated. The aqueous suspension was extracted 2×with EtOAc. The organics were dried over Na₂SO₄, filtered and evaporatedto a clear oil. Silica gel chromatography (gradient elution, 30 to 100%ethyl acetate in hexane), provided EXAMPLE 212 as a white foam.(M+H)⁺=465.4

Example 213 4-Methylbenzyl4-({[4-(aminomethyl)benzoyl]amino}methyl)piperidine-1-carboxylate

[0415]

[0416] 4-Methylbenzyl4-{[(4-{[(tert-butoxycarbonyl)amino]methyl}benzoyl)amino]methyl}piperidine-1-carboxylate(EXAMPLE 544) (200 mg, 0.40 mmol) was dissolved in EtOAc (10 mL), cooledto 0° C., and gaseous HCl was bubbled in for 10 min. After 30 min., themixture was evaporated to give a fine white powder of the hydrochloridesalt of EXAMPLE 213.

[0417] (M+H)⁺=396.4

Example 214 4-Methylbenzyl4-[({4-[(acetylamino)methyl]benzoyl}amino)methyl]piperidine-1-carboxylate

[0418]

[0419] To a solution of EXAMPLE 213 (20 mg, 0.05 mmol), in CH₂Cl₂ (10mL) was added triethylamine (14 μL, 0.10 mmol) and acetyl chloride (7.2μL, 0.092 mmol). After 5 min, water was added and the product wasextracted into CH₂Cl₂. Evaporation gave EXAMPLE 214 as a white solid.(M+H)⁺=438.3

Example 215 4-methylbenzyl4-{[(4-{[(methoxycarbonyl)amino]methyl}benzoyl)amino]methyl}piperidine-1-carboxylate

[0420]

[0421] To a solution of EXAMPLE 213 (30 mg, 0.069mmol) in THF (5 mL) wasadded triethylamine (19.3 μL) and methylchloroformate (5.3 μL). Thereaction mixture was stirred for 3 h then concentrated. Water andsaturated sodium bicarbonate was added and the aqueous layer wasextracted with EtOAc. The organic layer was dried over Na₂SO₄, filteredand concentrated to a white solid. Silica gel chromatography (75% ethylacetate in hexane to 95:5:0.5 ethyl acetate:MeOH:NH₄OH) provided EXAMPLE215 as a white solid. (M+H)⁺=454.4

Example 216 Benzyl4-fluoro-4-{[(4-hydroxybenzoyl)amino]methyl}piperidine-1-carboxylate

[0422]

Step 1 Preparation of tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate

[0423]

[0424] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.50g, 2.51 mmol) in THF/DME (2:1, 6 mL) at 60° C. was addedtrimethylsulfoxonium iodide (0.58 g, 2.63 mmol) and sodium t-butoxide(0.25 g, 2.63 mmol). The reaction mixture was stirred at 60° C. for 30min, cooled to rt and concentrated. Water was added and the mixture wasextract with EtOAc twice. The combined organics were dried over Na₂SO₄,filtered and concentrated. Purification on silica gel (3:1,hexanes:EtOAc) gave tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylateas a clear oil that solidified upon standing.

Step 2 Preparation of benzyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

[0425]

[0426] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.0 g,32.8 mmol) in CH₂Cl₂ (14 mL) at −10° C. was added HF-pyridine (11.6 mL,82.1 mmol) portionwise. The reaction mixture was stirred for 10 min at−10° C., warmed to rt. After stirring for 16 h, the reaction wascarefully quenched with aqueous NaCO₃, and extracted with CH₂Cl₂. Theaquoues layer was concentrated to a white paste that was suspended inCH₂Cl₂ (100 mL). BOCOS (8.2 g, 32.8 mmol) was added and the mixture wasstirred at RT for 3 h. The reaction mixture was partitioned betweenEtOAc and H₂O, the organic layer was dried over Na₂SO₄, filtered andconcentrated. Purification on silica gel (10:1 to 1:1 hexanes:EtOAc)gave benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate as aclear oil.

Step 3 Preparation of benzyl4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate

[0427]

[0428] To a solution of benzyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) inCH₂Cl₂ (10 mL) at RT was added MsCl (0.29 mL, 3.7 mmol) and TEA (1.04mL, 7.5 mmol). The reaction mixture was stirred at RT for 5 min, andpartitioned between EtOAc and H₂O. The organic layer was dried overNa₂SO₄, filtered, concentrated and purified on silica gel (10:1 to 1:2hexanes:EtOAc) to give benzyl4-fluoro-4-[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate.

Step 4 Preparation of benzyl4-(azidomethyl)-4-fluoropiperidine-1-carboxylate

[0429]

[0430] To a solution of benzyl4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (1.3 g,3.7 mmol) in DMF (10 mL) at RT was added NaN₃ (2.4 g, 37.0 mmol). Thereaction mixture was heated to 110° C. and stirred for 60 h, cooled andpartitioned between EtOAc and H₂O. The organic layer was dried overNa₂SO₄, filtered, concentrated and purified on silica gel (10:1 to 1:2hexanes:EtOAc) to give benzyl4-(azidomethyl)-4-fluoropiperidine-1-carboxylate.

Step 5 Preparation of benzyl4-(aminomethyl)-4-fluoropiperidine-1-carboxylate

[0431]

[0432] To a solution of benzyl4-(azidomethyl)-4-fluoropiperidine-1-carboxylate (1.5 g, 5.1 mmol) inTHF (10 mL) at RT with added water (0.92 mL, 0.92 mmol) andtriphenylphosphine (4.3 g, 15.4 mmol). The reaction mixture was stirredfor 60 h, concentrated, dissolved in HCl (1M) and extracted with Et₂Ofour times. The aqueous layer was basified to pH 11 and extracted withEtOAc twice. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude mixture was chromatographed on silica gel(CH₂Cl₂ to 80:20:2 CH₂C12:MeOH:NH4OH) to give benzyl4-(aminomethyl)-4-fluoropiperidine-1-carboxylate.

Step 6 Benzyl4-fluoro-4-{[(4-hydroxybenzoyl)amino]methyl}piperidine-1-carboxylate

[0433]

[0434] 4-Hydroxy benzoic acid was coupled to benzyl4-(aminomethyl)-4-fluoropiperidine-1-carboxylate according to theprocedure for EXAMPLE 1.

[0435] (M+H)⁺=387.3

Example 217 Benzyl4-({[(2-amino-1,3-thiazol-5-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

[0436]

Step 1 Preparation of ethyl 2-amino-1,3-thiazole-5-carboxylate

[0437]

[0438] To a mixture of B-ethoxyacrylic acid ethyl ester (2.0 g, 13.9mmol) in 1:1 dioxane/water (15 mL) at −10°0 C. was added NBS (2.72 g,15.3 mmol). Thiourea (1.06 g, 13.9 mmol) was added and the mixture washeated to 80° C. and stirred for 1.5 h. The reaction mixture was cooledto 0° C. and 5 mL of saturated ammonium hydroxide was added. Aprecipitate formed in 15 min. The solid was filtered, washed with waterand dried under vacuum, yielding a light orange solid.

Step 2 Preparation of2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid

[0439]

[0440] To a solution of ethyl 2-amino-1,3-thiazole-5-carboxylate (1.88g, 10.9 mmol) in dioxane (100 mL) was added di-t-butyl dicarbonate (2.43g, 12.0 mmol) and 2N NaOH (16.4 mL, 32.8 mmol). The reaction mixture wasstirred 18 h. then concentrated in vacuo. The paste was partitionedbetween ethyl acetate and water, the layers were separated, and theaqueous re-extracted twice with ethyl acetate. The combined organicswere dried over anhydrous sodium sulfate and concentrated to give anoil. The product was preabsorbed onto silica gel and columnchromatography (10 to 30% ethyl acetate in hexanes) afforded 3 g whitesolid. The solid was added to a solution of lithium hydroxide (0.5 g) inwater/TBF (1:1, 100 mL). The mixture was heated at 45° C. for 3d. Theorganics were evaporated, and the product was partitioned between ethylacetate and water. The aqueous layer was then acidified to pH˜4 with 6NHCl and filtered to obtain an off white solid.

Step 3 Preparation of benzyl4-{[({2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-5-yl}carbonyl)amino]methyl}piperidine-1-carboxylate

[0441]

[0442] 2-[(tert-Butoxycarbonyl)amino]-1,3-thiazole-5-carboxylic acid wascoupled to benzyl 4-(aminomethyl)piperidine-1-carboxylate according tothe procedure for EXAMPLE 1.

Step 4 Benzyl4-({[(2-amino-1,3-thiazol-5-yl)carbonyl]amino}methyl)piperidine-1-carboxylate

[0443]

[0444] EXAMPLE 217 was prepared from benzyl4-{[({2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-5-yl}carbonyl)amino]methyl}piperidine-1-carboxylateusing the procedure for EXAMPLE 174, Step3.

[0445] (M+H)⁺=375.3

Example 2184-Hydroxy-N-{[1(4-methylbenzyl)piperidin-4-yl]methyl}benzamide

[0446]

[0447] To a solution of 4-hydroxy-N-piperidin-4-ylmethyl-benzamide(EXAMPLE 154, Step 1) (50 mg, 0.21 mmol) in MeOH (3 mL) was added4-methylbenzaldehyde (25 mg, 0.21 mmol) and sodium cyanoborohydride (40mg, 0.64 mmol). The reaction mixture was stirred at rt for 15 h,concentrated and purified by reverse-phase HPLC. (M+H)⁺=339.2

[0448] The following Examples were prepared utilizing appropriateprocedures from examples described above. EX. Structure Name MS (M⁺ + 1)219.

4-{[(3-Methyl-3H-imidazole-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-fluoro-benzyl ester 375.3 220.

4-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acidbenzyl- methyl-amide 382.4 221.

N-[1-(4-Benzyloxy-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-4-hydroxy- benzamide 425.2 222.

1H-Pyrrole-3-carboxylic acid [1-(4- benzyloxy-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-amide 398.2 223.

4-{[(6-Hydroxy-pyrazine-2-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 371.3 224.

1H-Pyrazole-4-carboxylic acid [1-(3-p-tolyl-propionyl)-piperidin-4-ylmethyl]- amide 355.3 225.

1H-Pyrazole-4-carboxylic acid (1- benzyl-piperidin-4-ylmethyl)-amide299.3 226.

3-Hydroxy-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 385.3 227.

N-(1-Benzyl-piperidin-4-ylmethyl)-4- hydroxy-benzamide 325.3 228.

4-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylicacid furan-3-ylmethyl ester 333.2 229.

1H-Pyrrole-3-carboxylic acid [1-(3- phenyl-propionyl)-piperidin-4-ylmethyl]-amide 340.3 230.

4-Fluoro-4-{[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester374.3 231.

4-[(4-Hydroxy-benzoylamino)-methyl]- 3-methoxy-piperidine-1-carboxylicacid benzyl ester 399.3 232.

1H-Pyrrole-3-carboxylic acid [1-(3-phenyl-propyl)-piperidin-4-ylmethyl]- amide 326.3 233.

1H-Pyrrole-3-carboxylic acid [1-(2- phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 352.3 234.

4-[(4-Hydroxy-benzoylamino)-methyl]- 4-methyl-piperidine-1-carboxylicacid benzyl ester 383.3 235.

4-[(4-Hydroxy-benzoylamino)-methyl]- 4-phenyl-piperidine-1-carboxylicacid benzyl ester 445.3 236.

4-{[(1H-Indole-5-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidbenzyl ester 392.3 237.

1H-Indole-5-carboxylic acid [1-(2- phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide 426.3 238.

4-{[(2-Oxo-2,3-dihydro-benzooxazole-6-carbonyl)-amino]-methyl}-piperidine- 1-carboxylic acid benzyl ester239.

4-{[(1H-Indole-6-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidbenzyl ester 392.3 240.

1H-Indole-6-carboxylic acid [1-(2- phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amide 426.3 241.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidpyridin-4-ylmethyl ester 343.2 242.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidthiophen-2-ylmethyl ester 348.2 243.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid1- methyl-1H-imidazol-4-yl methyl ester 346.2 244.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}1-piperidine-1-carboxylicacid thiazol-4-ylmethyl ester 349.2 245.

4-{[(1-Methyl-1H-pyrrole-3-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 370.3 246.

3-Hydroxy-4-[(4-hydraxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 385.3 247.

3-Hydroxy-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 385.3 248.

4-}[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid4- fluoro-benzyl ester 360.2 249.

4-}[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid4- iodo-benzyl ester 468.2 250.

4-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid4-iodo- benzyl ester 495.2 251.

4-Fluoro-4-{[(1H-pyrrole-3-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 360.2 252.

N-(1-Benzyl-4-hydroxy-piperidin-4- ylmethyl)-4-hydroxy-benzamide 341.2253.

4-Hydroxy-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 385.2 254.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidthiazol-2-ylmethyl ester 349.2 255.

4-Amino-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 384.3 256.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid2- methyl-thiophen-3-ylmethyl ester 362.2 257.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid2,5-dichloro-thiophen-3-yl methyl ester 416.1 258.

4-Hydroxy-N-[4-hydroxy-1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-benzamide 369.2 259.

4-Hydroxy-N-(4-hydroxy-1-phenethyl- piperidin-4-ylmethyl)-benzamide355.2 260.

4-[(4-Benzyloxy-benzoylamino)- methyl]-3-hydroxy-piperidine-1-carboxylic acid benzyl ester 475.3 261.

1H-Pyrrole-3-carboxylic acid [1-(3-p-tolyl-propionyl)-piperidin-4-ylmethyl]-amide 354.3 262.

4{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid5- methyl-thiophen-2-ylmethyl ester 362.2 263.

3-Hydroxy-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 385.2 264.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidcyclopropylmethyl ester 306.2 265.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidcyclopentylmethyl ester 334.2 266.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid2,5-dimethyl-thiophen-3-yl methyl ester 376.1 267.

1H-Pyrrole-3-carboxylic acid [1-(4-chloro-benzyl)-piperidin-4-ylmethyl]-amide 332.2 268.

1H-Pyrrole-3-carboxylic acid [1-(5-methyl-thiophen-2-ylmethyl)-piperidin- 4-ylmethyl]-amide 318.2 269.

1H-Pyrrole-3-carboxylic acid [1-(3-fluoro-benzyl)-piperidin-4-ylmethyl]-amide 316.2 270.

1H-Pyrrole-3-carboxylic acid [1-(2,5- dimethyl-thiophen-3-ylmethyl)-piperidin-4-ylmethyl]-amide 332.2 271.

4-{[(1-Methyl-1H-pyrrole-3-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-fluoro-benzyl ester 374.2 272.

4-Hydroxy-N-[1-(2,4,6-trimethyl- benzenesulfonyl)-piperidin-4-ylmethyl]-benzamide 416.2 273.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidbicyclo[2.2.1]hept-2-ylmethyl ester 360.2 274.

4-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid2- methyl-cyclopropylmethyl ester 320.2 275.

N-[1-(4-Fluoro-benzyl)-piperidin-4- ylmethyl]-4-hydroxy-benzamide 343.2276.

N-[1-(4-Chloro-benzyl)-piperidin-4- ylmethyl]-4-hydroxy-benzamide 359.1277.

4-Hydroxy-N-[1-(1H-pyrrol-2- ylmethyl)-piperidin-4-ylmethyl]-benzamide314.2 278.

4-Hydroxy-N-[1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-ylmethyl]-benzamide 345.2 279.

4-Fluoro-4-{[(1H-pyrrole-3-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 374.2 280.

4-Fluoro-4-{[(2H-pyrazole-3- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 375.2 281.

4-Fluoro-4-{[(1H-pyrazole-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 375.2 282.

4-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid5-methyl- thiophen-2-ylmethyl ester 411.2 283.

4-Fluoro-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid 4-methyl-beuzyl ester 401.2 284.

4-Fluoro-4-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid 4-chloro-benzyl ester 421.2 285.

4-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylicacid 5- methyl-thiophen-2-ylmethyl ester 363.1 286.

4-Hydroxy-N-[3-hydroxy-1-(3-phenyl-propyl)-piperidin-4-ylmethyl]-benzamide 369.2 287.

4-Hydroxy-N-[3-hydroxy-1-(4-methyl-benzyl)-piperidin-4-ylmethyl]-benzamide 355.2 288.

4-Hydroxy-N-[3-hydroxy-1-(5-methyl- thiophen-2-ylmethyl)-piperidin-4-ylmethyl]-benzamide 361.1 289.

4-Hydroxy-N-[1-(2-p-tolyloxy-acetyl)- piperidin-4-ylmethyl]-benzamide383.2 290.

4-{[(2-Amino-pyridine-4-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 383.2 291.

N-{1-[2-(4-Chloro-phenoxy)-acetyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide 403.2 292.

N-{1-[2-(4-Fluoro-phenoxy)-acetyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide 387.3 293.

4-{[(2-Methylamino-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 397.2 294.

4-{[(2-Dimethylamino-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 411.3 295.

4-{[(1H-Pyrrole-3-carbonyl)-aminol]- methyl}-piperidine-1-carboxylicacid 4- chloro-benzyl ester 376.3 296.

4-{[(2-Benzylamino-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzy ester 473.3 297.

4-{[(2-Pentylamino-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 453.4 298.

4-({[2-(2-Fluoro-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 491.3 299.

4-({[2-(3-Fluoro-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 491.3 300.

4-({[2-(4-Fluoro-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 491.3 301.

4-Fluoro-4-{[(1H-pyrrole-3-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-fluoro-benzyl ester 378.2 302.

4-{[(2-Propylamino-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-beuzyl ester 425.3 303.

4-{[(2-Butylamino-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 439.3 304.

4-{[(2-Isobutylamino-pyridine-4- carbonyl)-aminol]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 439.3 305.

4-{[(2-Cyclobutylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4-methyl-benzylester 437.3 306.

4-{[(2-Cyclopentylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4-methyl-benzylester 451.3 307.

4-{[(2-Cyclohexylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4-methyl-benzylester 465.3 308.

4-({[2-(Cyclohexyl-methyl-amino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 479.3 309.

4-({[2-(1-Ethyl-propylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine- 1-carboxylic acid 4-methyl-benzylester 453.3 310.

4-({[2-(2-Methoxy-1-methyl- ethylamino)-pyridine-4-carbonyl]-amino}-methyl)-piperidine-1- carboxylic acid 4-methyl-benzyl ester 455.3311.

4-{[(2-Pyrrolidin-1-yl-pyridine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4-methyl-benzylester 437.3 312.

4-{[(2-Azepan-1-yl-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 465.3 313.

4-(({2-[(Thiophen-2-ylmethyl)-amino]-pyridine-4-carbonyl}-amino)-methyl]- piperidine-1-carboxylic acid4-methyl- benzyl ester 479.2 314.

4-({[2-(2-Methyl-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 487.3 315.

4-({[2-(3-Methyl-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 487.3 316.

4-({[2-(4-Methyl-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 487.3 317.

4-({[2-(2-Chloro-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 507.3 318.

4-({[2-(3-Chloro-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 507.3 319.

4-({[2-(4-Chloro-benzylamino)- pyridine-4-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid 4-methyl- benzyl ester 507.3 320.

4-{[(2-Phenethylamino-Pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 487.3 321.

4-Hydroxy-N-[1-(2-phenyl- cyclopropanecarbonyl)-piperidin-4-ylmethyl]-benzamide 379.3 322.

4-Hydroxy-N-[1-(2-phenyl- cyclopropanecarbonyl)-piperidin-4-ylmethyl]-benzamide 379.3 323.

4-Hydroxy-N-{1-[2-(naphthalen-2- yloxy)-acetyl]-piperidin-4-ylmethyl}-benzamide 419.4 324.

N-{1-[2-(2-Chloro-phenoxy)-acetyl]- piperidin-4-ylmethyl}-4-hydroxy-benzamide 403.3 325.

4-Hydroxy-N-[1-(2-phenoxy-acetyl)- piperidin-4-ylmethyl]-benzamide 369.4326.

4-Hydroxy-N-[1-(2-phenoxy- propionyl)-piperidin-4-ylmethyl]- benzamide383.4 327.

4-Hydroxy-N-[1-(2-phenylsulfanyl-acetyl)-piperidin-4-ylmethyl]-benzamide 385.3 328.

4-[(3-Fluoro-4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid 4-fluoro-benzyl ester 405.3 329.

4-{[(Pyrimidine-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid4- methyl-benzyl ester 369.4 330.

4-[(2,3,5,6-Tetrafluoro-4-hydroxy- benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester 441.3 331.

4-{[(Pyrimidine-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid4- fluoro-benzyl ester 373.4 332.

4-{[(2-Cyano-pyridrne-4-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 379.4 333.

4-[(4-Amino-benzoylamino)-methyl]- pipendine-1-carboxylic acid 4-fluoro-benzyl ester 386.4 334.

4-{[(Thiazole-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid4- fluoro-benzyl ester 378.4 335.

4-{[([1,2,5]Thiadiazole-3-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-fluoro-benzyl ester 379.4 336.

4-[(3-Acetyl-4-hydroxy-benzoylamino)- methyl]-piperidine-1-carboxylicacid benzyl ester 411.4 337.

4-{[(3-Amino-6-chloro-pyridazine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester404.4 338.

4-{[(3-Chloro-6-hydroxy-pyridazine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester405.3 339.

4-{[(3-Hydroxy-pyridine-4-Carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 370.4 340.

4-{[(2-Fluoro-pyridine-4-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 386.4 341.

4-{[(6-Methyl-2-oxo-1,2-dihydro- pyridine-4-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 384.4 342.

4-{[(2-Benzylamino-pyrimidine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 460.4 343.

4-{[(2-Chloro-6-methylamino-pyridine-4-carbonyl)-amino]-methyl}-piperidine- 1-carboxylic acid benzyl ester417.4 344.

4-({[2-Chloro-6-(2,4-dimethoxy- benzylamino)-pyridine-4-Carbonyl]-amino}-methyl)-piperidine-1- carboxylic acid benzyl ester 553.5 345.

4-{[(2-Amino-6-chloro-pyridine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 403.4 346.

4-[(3,5-Difluoro-4-hydroxy- benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester 405.4 347.

4-{[(4-Amino-2-hydroxy-pyrimidine-5-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester386.4 348.

4-[(4-Carboxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid4-methyl- benzyl ester 411.4 349.

4-[2,5-Difluoro-4-hydroxy- benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester 405.4 350.

4-{[(Thiazole-4-carbonyl)-amino]- methyl}-piperidine-1-calboxylic acid4- iodo-benzyl ester 486.3 351.

Pyrimidine-4-carboxylic acid [1-(2- phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 365.4 352.

Thiazole-4-carboxylic acid [1-(2- phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 370.4 353.

4-{[(5-Hydroxy-pyrimidine-2- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 371.4 354.

4-[(4-Acetyl-benzoylamino)-methyl]- piperidine-1-carboxylic acid4-methyl- benzyl ester 409.3 355.

2-Fluoro-N-[1-(2-phenyl- cyclopropanecarbonyl)-piperidin-4-ylmethyl]-isonicotinamide 382.4 356.

Pyrimidine-4-carboxylic acid [1-(2- phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 365.4 357.

4-{[(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester408.3 358.

Thiazole-4-carboxylic acid [1-(2- phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 370.3 359.

4-{[(2-Oxo-1,2,3,4-tetrahydro- quinoline-6-carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 422.4 360.

4-{[(5-Amino-2-methyl-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester384.4 361.

4-{[4-(1-Hydroxyimino-ethyl)- benzoylamino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 424.3 362.

4-Cyano-N-[1-(2-phenyl- cyclopropanecarbonyl)-piperidin-4-ylmethyl]-benzamide 388.3 363.

4-{[(2-Oxo-1,2-dihydro-quinoline-6-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid benzyl ester420.3 364.

4-[(4-Formyl-benzoylamino)-methyl]- piperidine-1-carboxylic acid4-methyl- benzyl ester 395.3 365.

Thiazole-4-carboxylic acid {1-[2-(2-fluoro-phenyl)-cyclopropanecarbonyl]- piperidin-4-ylmethyl}-amide 388.2366.

Thiazole-4-carboxylic acid {1-[2-(2,6- difluoro-phenyl)-cyclopropanecarbonyl]-piperidin-4- ylmethyl}-amide 406.2 367.

2-Fluoro-N-{1-[2-(2-fluoro-phenyl)- cyclopropanecarbonyl]-piperidin-4-ylmethyl}-isonicotinamide 400.3 368.

N-{1-[2-(2,6-Difluoro-phenyl)- cyclopropanecarbonyl]-piperidin-4-ylmethyl}-2-fluoro-isonicotinamide 418.3 369.

4-{[(2-Methanesulfonyl-pyrimidine-4-carbonyl)-amino]-methyl}-piperidine-1- carboxylic acid 4-methyl-benzylester 448.2 370.

4-{[(2-Amino-pyrimidine-4-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 384.3 371.

2-Methanesulfonyl-pyrimidine-4- carboxylic acid [1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4- ylmethyl]-amide 443.3 372.

2-Amino-pyrimidine-4-carboxylic acid [1-(2-phenyl-cyclopropanecarbonyl)-piperidin-4-ylmethyl]-amide 380.2 373.

4-{[(2-Ethoxy-thiazole-5-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 404.2 374.

4-{[(6-Chloro-pyridine-2-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 388.2 375.

4-{[(2-Methylamino-pyrimidine-4- carbonyl)-amino]-methyl}-piperidine-1-carboxylic acid 4-methyl-benzyl ester 398.3 376.

4-{[(6-Amino-pyridine-2-carbonyl)- amino]-methyl}-piperidine-1-carboxylic acid benzyl ester 369.2 377.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid benzylester 369.2 378.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid4-methyl- benzyl ester 383.3 379.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid4-fluoro- benzyl ester 387.2 380.

4-Hydroxy-N-[1-(3-phenyl-propyl)- piperidin-3-ylmethyl]-benzamide 353.3381.

4-Hydroxy-N-(1-phenethyl-piperidin-3- ylmethyl)-benzamide 339.3 382.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid benzylester 369.3 383.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperidine-1-carboxylic acid benzylester 369.3 384.

4-Hydroxy-N-[3-hydroxy-1-(3-phenyl-propyl)-piperidin-3-ylmethyl]-benzamide 369.3 385.

4-Hydroxy-N-(3-hydroxy-1-phenethyl- piperidin-3-ylmethyl)-benzamide355.2 386.

3-Hydroxy-3-[(4-hydroxy- benzoylamino)-methyl]-piperidine-1- carboxylicacid benzyl ester 385.2 387.

3-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acidbenzyl ester 342.7 388.

3-{[(2H-Pyrazole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylicacid benzyl ester 343.2 389.

3-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylicacid benzyl ester 343.2 390.

3-{-(1H-Pyrro1e-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylic acid4- methyl-benzyl ester 356.2 391.

3-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-piperidine-1-carboxylicacid 4- methyl-benzyl ester 357.2 392.

3-{[(2H-Pyrazole-3-carbonyl)-amino]- methyl}-piperidine-1-carboxylicacid 4- methyl-benzyl ester 357.2 393.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperazine-1-carboxylic acid benzylester 370.2 394.

3-[(4-Hydroxy-benzoylamino)-methyl]- 4-methyl-piperazine-1-carboxylicacid benzyl ester 384.3 395.

4-Hydroxy-N-[4-(3-phenyl-propyl)- piperazin-2-ylmethyl]-benzamide 354.2396.

4-Hydroxy-N-(4-phenethyl-piperazin-2- ylmethyl)-benzamide 340.3 397.

4-Hydroxy-N-[4-(3-phenyl-propionyl)- piperazin-2-ylmethyl]-benzamide368.3 398.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperazine-1-carboxylic acid benzylester 370.2 399.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperazine-1-carboxylic acid benzylester 370.2 400.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperazine-1-carboxylic acid4-fluoro- benzyl ester 388.2 401.

3-[(4-Hydroxy-benzoylamino)-methyl]- piperazine-1-carboxylic acid4-methyl- benzyl ester 384.2 402.

3-{[(2-Oxo-2,3-dihydro-benzooxazole- 6-carbonyl)-amino]-methyl}-piperazine-1-carboxylic acid benzyl ester 411.2 403.

4-Hydroxy-N-(4-naphthalen-1- ylmethyl-piperazin-2-ylmethyl)- benzamide368.4 404.

4-Hydroxy-N-(4-naphthalen-2- ylmethyl-piperazin-2-ylmethyl)- benzamide354.2 405.

3-[(4-Hydroxy-benzoylamino)-methyl]- pyrrolidine-1-carboxylic acidbenzyl ester 376.3 406.

3-[(4-Hydroxy-benzoylamino)-methyl]- pyrrolidine-1-carboxylic acidbenzyl ester 376.3 407.

3-[(4-Hydroxy-benzoylamino)-methyl]- pyrrolidine-1-carboxylic acidbenzyl ester 355.3 408.

3-[(4-Hydroxy-benzoylamino)-methyl]- pyrrolidine-1-carboxylic acid4-methyl- benzyl ester 369.3 409.

3-[(4-Hydroxy-benzoylamino)-methyl]- pyrrolidine-1-carboxylic acid4-fluoro- benzyl ester 373.3 410.

N-(1-Benzyl-pyrrolidin-3-ylmethyl)-4- hydroxy-benzamide 311.4 411.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid benzylester 371.2 412.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-methyl- benzyl ester 385.7 413.

4-Hydroxy-N-[-(3-phenyl-propyl)- morpholin-2-ylmethyl]-benzamide 355.2414.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-chloro- benzyl ester 405.1 415.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-fluoro- benzyl ester 389.1 416.

4-Hydroxy-N-(4-phenethyl-morpholin- 2-ylmethyl)-benzamide 341.1 417.

4-Hydroxy-N-(4-phenylacetyl- morpholin-2-ylmethyl)-benzamide 355.2 418.

4-Hydroxy-N-[4-(3-phenyl-propionyl)- morpholin-2-ylmethyl]-benzamide369.2 419.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-fluoro- benzyl ester 389.3 420.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-chloro- benzyl ester 405.1 421.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid benzylester 371.1 422.

4-Hydroxy-N-[4-(3-phenyl-propionyl)- morpholin-2-ylmethyl]-benzamide369.2 423.

4-Hydroxy-N-(4-phenethyl-morpholin- ylmethyl)-benzamide 341.2 424.

2-{[(Pyridine-4-carbonyl)-amino]- methyl}-morpholine-4-carboxylic acidbenzyl ester 56.2 425.

2-[(3-Fluoro-4-hydroxy- benzoylamino)-methyl]-morpholine-4- carboxylicacid benzyl ester 389.1 426.

2-[(2-Fluoro-4-hydroxy- benzoylamino)-methyl]-morpholine-4- carboxylicacid benzyl ester 389.1 427.

2-](4-Hydroxy-3-methyl- benzoylamino)-methyl]-morpholine-4- carboxylicacid benzyl ester 385.2 428.

2-{[(3-Amino-pyridine-4-carbonyl)- amino]-methyl}-morpholine-4-carboxylic acid benzyl ester 371.1 429.

2-{[(1H-Pyrazole-4-carbonyl)-amino]- methyl}-morpholine-4-carboxylicacid benzyl ester 345.2 430.

2-{[(6-Hydroxy-pyridine-3-carbonyl)- amino]-methyl}-morpholine-4-carboxylic acid benzyl ester 372.2 431.

2-{[(2-Oxo-2,3-dihydro-benzooxazole- 6-carbonyl)-amino]-methyl}-morpholine-4-carboxylic acid benzyl ester 412.1 432.

2-[(4-Cyano-benzoylamino)-methyl]- morpholine-4-carboxylic acid benzylester 380.2 433.

2-[(4-Benzoyloxy-benzoylamino)- methyl]-morpholine-4-carboxylic acidbenzyl ester 475.2 434.

2-[(4-Methanesulfonylamino- benzoylamino)-methyl]-morpholine-4-carboxylic acid benzyl ester 448.1 435.

3-Fluoro-4-hydroxy-N-(4-phenethyl- morpholin-2-ylmethyl)-benzamide 359.2436.

2-Fluoro-4-hydroxy-N-(4-phenethyl- morpholin-2-ylmethyl)-benzamide 359.1437.

4-Hydroxy-3-methyl-N-(4-phenethyl- morpholin-2-ylmethyl)-benzamide 355.2438.

6-Hydroxy-N-(4-phenethyl-morpholin- 2-ylmethyl)-nicotinamide 342.2 439.

2-Oxo-2,3-dihydro-benzooxazole-6- carboxylic acid (4-phenethyl-morpholin-2-ylmethyl)-amide 382.1 440.

4-Cyano-N-(4-phenethyl-morpholin-2- ylmethyl)-benzamide 350.2 441.

Benzoic acid 4-[(4-phenethyl- morpholin-2-ylmethyl)-carbamoyl]- phenylester 445.2 442.

4-Methanesulfonylamino-N-(4- phenethyl-morpholin-2-ylmethyl)- benzamide418.1 443.

1H-Pyrazole-4-carboxylic acid (4- phenethyl-morpholin-2-ylmethyl)-amide341.2 444.

4-Hydroxy-N-[5-oxo-4-(3-phenyl- propyl)-morpholin-2-ylmethyl]-benzamide369.7 445.

4-Hydroxy-N-(5-oxo-4-phenethyl- morpholin-2-ylmethyl)-benzamide 355.6446.

N-{4-[2-(4-Fluoro-phenyl)-ethyl]- morpholin-2-ylmethyl}-4-hydroxy-benzamide 359.3 447.

2-{[(2-Oxo-2,3-dihydro-benzooxazole- 6-carbonyl)-amino]-methyl}-morpholine-4-carboxylic acid benzyl ester 412.3 448.

2-[(4-Methanesulfonylamino- benzoylamino)-methyl]-morpholine-4-carboxylic acid benzyl ester 448.3 449.

2-[(3-Fluoro-4-hydroxy-benzoylamino)- methyl]-morpholine-4-carboxylicacid benzyl ester 389.3 450.

2-[(4-Hydroxy-3-methyl- benzoylamino)-methyl]-morpholine-4- carboxylicacid benzyl ester 385.3 451.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-ethyl- benzyl ester 399.4 452.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidthiophen- 3-ylmethyl ester 377.2 453.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidthiophen- 2-ylmethyl ester 377.2 454.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidpyridin- 4-ylmethyl ester 372.2 455.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-isopropyl-benzyl ester 413.3 456.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-tert- butyl-benzyl ester 427.3 457.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid2-chloro- benzyl ester 405.2 458.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid3-chloro- benzyl ester 405.2 459.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid2-methyl- benzyl ester 385.3 460.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid3-methyl- benzyl ester 385.3 461.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidbenzo[1,3]dioxol-5-ylmethyl ester 415.3 462.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidphenethyl ester 385.3 463.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidbiphenyl- 4-ylmethyl ester 447.3 464.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 3-trifluoromethyl-benzyl ester 439.3 465.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-trifluoromethyl-benzyl ester 439.3 466.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid3-fluoro- benzyl ester 389.3 467.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-trifluoromethoxy-benzyl ester 455.3 468.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 3,4-dimethyl-benzyl ester 399.3 469.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 2,4-dimethyl-benzyl ester 399.3 470.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid1-phenyl- ethyl ester 385.3 471.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid1-phenyl- ethyl ester 385.3 472.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-methylsulfanyl-benzyl ester 417.3 473.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 3-trifluoromethoxy-benzyl ester 455.3 474.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 2-trifluoromethoxy-benzyl ester 455.3 475.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid6-chloro- pyridin-3-ylmethyl ester 406.2 476.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid6-methyl- pyridin-3-ylmethyl ester 386.3 477.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-cyclopropyl-benzyl ester 411.3 478.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidindan-2- yl ester 397.3 479.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid5-methyl- thiophen-2-ylmethyl ester 391.3 480.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 1-oxy-pyridin-4-ylmethyl ester 388.2 481.

4-Hydroxy-N-[4-(2-phenyl- cyclopropanecarbonyl)-morpholin-2-ylmethyl]-benzamide 381.3 482.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid3-fluoro- benzyl ester 389.4 483.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidbiphenyl- 4-ylmethyl ester 447.4 484.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid2-fluoro- benzyl ester 389.4 485.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-benzyloxy-benzyl ester 477.25 486.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 2,4-dichloro-benzyl ester 439.3 487.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 2,4-difluoro-benzyl ester 407.4 488.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 3,4-difluoro-benzyl ester 407.4 489.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-fluoro- 3-trifluoromethyl-benzyl ester 457.4 490.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid2-fluoro- 4-trifluoromethyl-benzyl ester 457.4 491.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 3,5-dichloro-benzyl ester 439.3 492.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 2,5-dichloro-benzyl ester 439.3 493.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 3-trifluoromethyl-benzyl ester 439.4 494.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid3-methyl- benzyl ester 385.4 495.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid3-chloro- benzyl ester 405.3 496.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-methylsulfanyl-benzyl ester 417.3 497.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid2-chloro- benzyl ester 405.3 498.

2-{[(5-Hydroxy-pyridine-2-carbonyl)- amino]-methyl}-morpholine-4-carboxylic acid 4-fluoro-benzyl ester 390.3 499.

2-[(3-Fluoro-4-hydroxy- benzoylamino)-methyl]-morpholine-4- carboxylicacid 4-fluoro-benzyl ester 407.3 500.

2-[(4-Hydroxy-benzoylamino)-methyl]- 5-methyl-morpholine-4-carboxylicacid benzyl ester 385.4 501.

2-[(4-Hydroxy-benzoylamino)-methyl]- 5-methyl-morpholine-4-carboxylicacid 4-methyl-benzyl ester 399.3 502.

2-[(3-Chloro-4-hydroxy- benzoylamino)-methyl]-morpholine-4- carboxylicacid 4-fluoro-benzyl ester 423.3 503.

2.[(3,5-Dichloro-4-hydroxy- benzoylamino)-methyl]-morpholine-4-carboxylic acid 4-fluoro-benzyl ester 457.2 504.

2-{[(6-Hydroxy-pyridazine-3- carbonyl)-amino]-methyl}-morpholine-4-carboxylic acid 4-fluoro-benzyl ester 391.4 505.

2-[(4-Hydroxy-benzoylamino)-methyl]- 5-methyl-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 403.4 506.

2-[(4-Hydroxy-benzoylamino)-methyl]- 5-methyl-morpholine-4-carboxylicacid benzyl ester 385.3 507.

2-[(4-Hydroxy-benzoylamino)-methyl]- 5-methyl-morpholine-4-carboxylicacid 4-methyl-benzyl ester 399.4 508.

2-(4-Hydroxy-benzoylamino)-methyl]- 5-methyl-morpholine-4-carboxylicacid 4-fluoro-benzyl ester 403.3 509.

2-[2,3-Difluoro-4-hydroxy- benzoylamino)-methyl]-morpholine-4-carboxylic acid 4-fluoro-benzyl ester 425.2 510.

2-[(3-Bromo-4-hydroxy- benzoylamino)-methyl]-morpholine-4- carboxylicacid 4-fluoro-benzyl ester 467.2 511.

2-[(2-Chloro-4-hydroxy- benzoylamino)-methyl]-morpholine-4- carboxylicacid 4-fluoro-benzyl ester 423.2 512.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidpyridin- 4-ylmethyl ester 372.3 513.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidpyridin- 3-ylmethyl ester 372.3 514.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acidpyridin- 2-ylmethyl ester 372.3 515.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid benzylester 371.3 516.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-fluoro- benzyl ester 389.3 517.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-chloro- benzyl ester 405.3 518.

2-[(4-Hydroxy-benzoylamino)-methyl]- morpholine-4-carboxylic acid 4-methanesulfinyl-benzyl ester 433.3 519.

2-[(4-Cyano-benzoylamino)-methyl]- morpholine-4-carboxylic acid4-fluoro- benzyl ester 398.4 520.

2-[(4-Hydroxymethyl-benzoylamino)- methyl]-morpholine-4-carboxylic acid4-fluoro-benzyl ester 403.4 521.

2-{[(2-Oxo-2,3-dihydro-1H-indole-5- carbonyl)-amino]-methyl}-morpholine-4-carboxylic acid benzyl ester 410.3 522.

2-{[(2-Oxo-1,2,3,4-tetrahydro- quinoline-6-carbonyl)-amino]-methyl}-morpholine-4-carboxylic acid benzyl ester 424.4 523.

4-Methylbenzyl 4-({[(2,5-dimethyl-1H- pyrrol-3-yl)carbonyl]amino}methyl)piperidine 1-carboxylate 370.2 524.

4-Methylbenzyl 4-{[(2-chloroisonicotinoyl)amino]methyl}piperidine-1-carboxylate 402.1 525.

Benzyl 4-({[(5-hydroxypyridin-2- yl)carbonyl]amino}methyl)piperidine-1-carboxylate 370.3 526.

Benzyl 4-({[4-hydroxy-3- (trifluoromethyl)benzoyl]amino}methyl)piperidine-1-carboxylate 437.4 527.

Benzyl 4-{[(2- fluoroisonicotinoyl)amino]methyl}piperidine-1-carboxylate372.4 528.

Benzyl 4-{[(2,3-difluoro-4-hydroxybenzoyl)amino]methyl}piperidine-1-carboxylate 405.3 529.

Benzyl 4-{[(pyridazin-4- ylcarbonyl)amino]methyl}piperidine-1-carboxylate 355.3 530.

Benzyl 4-{[(4-hydroxy-3-methoxybenzoyl)amino]methyl}piperidine-1-carboxylate 399.4 531.

Benzyl 4-{[(2,6-dichloroisonicotinoyl)amino]methyl}piperidine-1-carboxylate 423.3 532.

4-Methylbenzyl 4-({[4- (hydroxymethyl)benzoyl]amino}methyl)piperidine-1-carboxylate 397.4 533.

4-Methylbenzyl 4-({[4- (methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate 425.5 534.

4-Methylbenzyl 4-({[4-(1- hydroxyethyl)benzoyl]amino}methyl)piperidine-1-carboxylate 411.4 535.

4-Methylbenzyl 4-({[3- (methoxycarbonyl)benzoyl]amino}methyl)piperidine-1-carboxylate 425.4 536.

4-Methylbenzyl 4-({[4-(2- hydroxyethyl)benzoyl]amino}methyl)piperidine-1-carboxylate 411.3 537.

4-Methylbenzyl 4-({[4-(1H-imidazol-2- yl)benzoyl]amino}methyl)piperidine-1-carboxylate 433.3 538.

4-Methylbenzyl 4-({[4- (trifluoroacetyl)benzoyl]amino}methyl)piperidine-1-carboxylate 481.2 539.

4-Methylbenzyl 4-{[(4-{[(tert- butoxycarbonyl)amino]methyl}benzoyl)amino]methyl}piperidine-1- carboxylate 496.4 540.

4-Methylbenzyl 4-[({[2- (hydroxymethyl)-1,3-thiazol-4-yl]carbonyl}amino)methyl]piperidine- 1-carboxylate 404.2 541.

7-[(4-Hydroxy-benzoylamino)-methyl]- [1,4]oxazepane-4-carboxylic acid 4-methyl-benzyl ester 399.4 542.

7-[(4-Hydroxy-benzoylamino)-methyl]- [1,4]oxazepane-4-carboxylic acid 4-fluoro-benzyl ester 403.4 543.

7-{[(1H-Pyrrole-3-carbonyl)-amino]- methyl}-[1,4]oxazepane-4-carboxylicacid benzyl ester 358.3 544.

7-[(4-Hydroxy-benzoylamino)-methyl]- [1,4]oxazepane-4-carboxylic acid 4-chloro-benzyl ester 419.4 545.

4-[(4-Hydroxy-benzoylamino)-methyl]- azepane-1-carboxylic acid benzylester 383.4 546.

4-[(4-Hydroxy-benzoylamino)-methyl]- azepane-1-carboxylic acid benzylester 383.4 547.

4-[(4-Hydroxy-benzoylamino)-methyl]- azepane-1-carboxylic acid benzylester 383.4 548.

7-[(4-Hydroxy-benzoylamino)-methyl]- [1,4]oxazepane-4-carboxylic acidbenzyl ester 385.4 549.

7-[(4-Hydroxy-benzoylamino)-methyl]- [1,4]oxazepane-4-carboxylic acidbenzyl ester 385.4

What is claimed is:
 1. A compound having the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein Non Ar is anonaromatic 5-7 membered ring containing a) 1 nitrogen ring atom, b) 2nitrogen ring atoms, c) 1 nitrogen and 1 oxygen ring atom, or d) 1nitrogen and 1 sulfur ring atom, wherein the remaining ring atoms arecarbon; A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl—N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen; or A is pyrrolyl, imidazolyl,pyrazolyl, triazolyl, thiophenyl, thiazolyl, thiadiazolyl, oxazolyl, orisoxazolyl, each optionally substituted with 1-3 substituents, eachsubstituent independently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, —C₁₋₄alkoxyl, phenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₁₋₄ hydroxyalkyl; or A is pyridyl, pyradazinyl, pyrimidinyl, orpyrazinyl, each optionally substituted with 1-5 substituents; eachsubstituent independently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, phenyl, pyrrolidinyl, azepanyl, —C₁₋₄hydroxyalkyl,—C₁₋₄alkoxy, (CH₃)₂N—(CH₂)₂—NH—, —SO₂—C₁₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₃₋₆cycloalkyl)(C₀₋₅alkyl),—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₁₋₄alkyloxyC₁₋₄alkyl),—N(C₀₋₅alkyl)-C₀₋₄alkyl-phenyl(C₁₋₄alkoxyl)₀₋₃,—N(C₀₋₅alkyl)—C₀₋₄alkylthiaphenyl, dimethoxyphenyl-CH₂—NH—; any phenyloptionally substituted with 1-5 —OH, halogen, or C₁₋₄alkyl; any alkyloptionally substituted with 1-5 —OH or halogen; or the substituent takenwith a neighboring bond is ═O; or A is pyrrolophenyl, imidazolophenyl,pyrazolophenyl, triazolophenyl, pyridinoirnidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl,indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl,each optionally substituted with 1-5 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or—CN; B is aryl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,heteroaryl(CH₂)₁₋₃—O—(CH₂)₀₋₂—C(O)—, indanyl(CH₂)₀₋₃—O—(CH₂)₀₋₂—C(O)—,aryl(CH₂)₁₋₃—C(O)—(CH₂)₀₋₂—, aryl-cyclopropyl-C(O)—(CH₂)₀₋₂—,heteroaryl(CH₂)₁₋₃—C(O)—, aryl(CH₂)₁₋₃—, heteroaryl(CH₂)₁₋₃—,aryl(CH₂)₁₋₃—NH—C(O)—, aryl(CH₂)₁₋₃—NH—C(NCN)—, aryl(CH₂)₁₋₃—SO₂—,aryl(CH₂)₀₋₃—S—(CH₂)₀₋₂—C(O)—, or heteroaryl(CH₂)₁₋₃—SO₂— wherein any ofthe aryl or heteroaryl is optionally substituted by 1-5 substituents,each substituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, phenyl, —O—C₁₋₄alkylphenyl, —S(O)—C₁₋₄alkyl, bromo,fluoro, chloro, or 2 substituents together form methylene dioxy; any(CH₂) optionally is substituted with C₁₋₂alkyl; or

 wherein the phenyl is optionally substituted by 1-3 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₆cycloalkyl, C₁₋₄alkoxy,trifluoromethyl, bromo, fluoro, or chloro; and X is H, OH, F, C₁₋₄alkyl,C₁₋₄alkoxy, —N(C₀₋₅alkyl)(C₀₋₅alkyl), phenyl, or ═O.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein Non Ar is a nonaromatic 6 membered ring containing 1 nitrogenring atom, wherein the remaining ring atoms are carbon.
 3. The compoundaccording to claim 2, or a pharmaceutically acceptable salt thereof,wherein A is a phenyl optionally substituted with 1-5 substituents, eachsubstituent independently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen,—OH, —CN, imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)—C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen.
 4. The compound according to claim2, or a pharmaceutically acceptable salt thereof, wherein A is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl, thiadiazolyl,oxazolyl, or isoxazolyl, each optionally substituted with 1-3substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, phenyl, —C₁₋₄hydroxyalkyl. 5.The compound according to claim 2, or a pharmaceutically acceptable saltthereof, wherein A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl,each optionally substituted with 1-3 substituents, each substituentindependently is —C₁₋₄alkyl, —C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,phenyl, —C₁₋₄hydroxyalkyl, —C₁₋₄alkoxy, (CH₃)₂N—(CH₂)₂—NH—,—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl), dimethoxyphenyl-CH₂—NH—, or thesubstituent taken with a neighboring bond is ═O.
 6. The compoundaccording to claim 2, or a pharmaceutically acceptable salt thereof,wherein A is pyrrolophenyl, imidazolophenyl, pyrazolophenyl,triazolophenyl, pyridinoimidazolyl, naphthyridinyl,tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl,benzothiazolyl, benzoimidazolyl, or purinyl, each optionally substitutedwith 1-3 substituents, each substituent independently is —C₁₋₄alkyl,—C₃₋₇cycloalkyl, —CF₃, halogen, —OH, or —CN.
 7. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, wherein NonAris a nonaromatic 5 membered ring containing 1 nitrogen ring atom,wherein the remaining ring atoms are carbon.
 8. The compound accordingto claim 7, or pharmaceutically acceptable salts thereof, wherein A is aphenyl optionally substituted with 1-5 substituents, each substituentindependently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,imidazolyl, —CO₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)-C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O-C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen.
 9. The compound according to claim1, or a pharmaceutically acceptable salt thereof, wherein NonAr is anonaromatic 6 membered ring containing 2 nitrogen ring atoms, whereinthe remaining ring atoms are carbon.
 10. The compound according to claim9, or pharmaceutically acceptable salts thereof, wherein A is a phenyloptionally substituted with 1-5 substituents, each substituentindependently is C₁₋₄alkyl, C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN,imidazolyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl,—C(O)—C₀₋₄alkyl, —C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl,—O—C(O)—C₀₋₄alkylphenyl, —C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)O—C₁₋₄alkyl,or —NHSO₂—C₁₋₄alkyl, —O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyloptionally substituted with 1-6 —OH or halogen.
 11. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein NonAr is a nonaromatic 6 membered ring containing 1 nitrogen and1 oxygen ring atom, wherein the remaining ring atoms are carbon.
 12. Thecompound according to claim 11, or a pharmaceutically acceptable saltthereof, wherein A is a phenyl optionally substituted with 1-5substituents, each substituent independently is C₁₋₄alkyl,C₃₋₇cycloalkyl, —CF₃, halogen, —OH, —CN, imidazolyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)(C₀₋₅alkyl), —O—C₁₋₄alkyl, —C(O)—C₀₋₄alkyl,—C(O)—O—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkyl, —O—C(O)—C₀₋₄alkylphenyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₅alkyl)-C(O)—O—C₁₋₄alkyl, or —NHSO₂—C₁₋₄alkyl,—O—C₁₋₄alkylphenyl, or hydroxyiminoethyl; any alkyl optionallysubstituted with 1-6 —OH or halogen.
 13. The compound according to claim1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 16. The corn woundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1, wherein said compound is

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising an inert carrier and an effective amount of acompound according to claim
 1. 23. The pharmaceutical compositionaccording to claim 22 useful for the treatment of pain.
 24. Thepharmaceutical composition according to claim 22 useful for thetreatment of migraine, depression, anxiety, schizophrenia, Parkinson'sdisease, or stroke.
 25. A method of treating pain comprising a step ofadministering to one in need of such treatment an effective amount of acompound according to claim
 1. 26. A method of treating migraine,depression, anxiety, schizophrenia, Parkinson's disease, or strokecomprising a step of administering to one in need of such treatment aneffective amount of a compound according to claim
 1. 27. A methods oftreatment of glaucoma or tinitis comprising a step of administering toone in need of such treatment an effective amount of a compoundaccording to claim 1.